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Cellular Signaling Mechanisms in Pancreatic Apoptosis

  • Chapter
Apoptosis in Carcinogenesis and Chemotherapy

Abstract

It is evident that various types of tumor cells use different mechanisms to inhibit apoptosis. Recent increased understanding of the many factors involved in the apoptotic process has identified potential targets for the restoration of the apoptotic response in pancreatic tumor cells. The ultimate goal is to develop effective therapeutic strategies to control this devastating disease. The aim of this chapter is to review signaling pathways involved in apoptosis by providing an account of the signaling molecules involved. This chapter reviews the literature on traditional apoptotic signaling pathways with special emphasis on pancreatic cancer. Involvement of G-protein coupled receptors and inositol phosphates in pancreatic apoptosis is also reviewed. Finally we have reviewed the literature on nutritional impacts on pancreatic apoptosis as an example of an environmental risk factor for pancreatic cancer. Knowledge about diverse effects on signaling molecules may serve as a basis for pancreatic cancer chemotherapeutic applications focused on apoptotic mechanisms.

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References

  • Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    PubMed  CAS  Google Scholar 

  • Adrian TE (2007) Inhibition of pancreatic cancer cell growth. Cell Mol Life Sci 64:2512–2521

    PubMed  CAS  Google Scholar 

  • Agarwal C, Dhanalakshmi S, Singh RP, Agarwal R (2003) Inositol hexaphosphate inhibits constitutive activation of NF- kappa B in androgen-independent human prostate carcinoma DU145 cells. Anticancer Res 23:3855–3861

    PubMed  CAS  Google Scholar 

  • Agarwal C, Dhanalakshmi S, Singh RP, Agarwal R (2004) Inositol Hexaphosphate Inhibits Growth and Induces G1 Arrest and Apoptotic Death of Androgen-Dependent Human Prostate Carcinoma LNCaP Cells. Neoplasia 6:646–659

    PubMed  CAS  Google Scholar 

  • Ali N, Agrawal DK (1994) Guanine nucleotide binding regulatory proteins: their characteristics and identification. J Pharmacol Toxicol Methods 32:187–196

    PubMed  CAS  Google Scholar 

  • Ali N, Craxton A, Shears SB (1993) Hepatic Ins(1,3,4,5)P4 3-phosphatase is compartmentalized inside endoplasmic reticulum. J Biol Chem 268:6161–6167

    PubMed  CAS  Google Scholar 

  • Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921

    PubMed  CAS  Google Scholar 

  • Asanuma K, Kobayashi D, Furuya D, Tsuji N, Yagihashi A, Watanabe N. (2002) A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res 93:1057–1062

    PubMed  CAS  Google Scholar 

  • Asanuma K, Moriai R, Yajima T, Yagihashi A, Yamada M, Kobayashi D, Watanabe N (2000) Survivin as a radioresistance factor in pancreatic cancer. Jpn J Cancer Res 91:1204–1209

    PubMed  CAS  Google Scholar 

  • Ashkenazi A, Dixit VM. (1999) Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11:255–260

    PubMed  CAS  Google Scholar 

  • Baell JB, Huang DC (2002) Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 64:851–863

    PubMed  CAS  Google Scholar 

  • Baker CH, Trevino JG, Summy JM, Zhang F, Caron A, Nesbit M, Gallick GE, Fidler IJ (2006) Inhibition of PDGFR phosphorylation and Src and Akt activity by GN963 leads to therapy of human pancreatic cancer growing orthotopically in nude mice. Int J Oncol 29:125–138

    PubMed  CAS  Google Scholar 

  • Bardeesy N (2005) Molecular signaling pathways in pancreatic cancer in “Pancreatic Cancer, Chapter 4”. In: Van Wolff, DD, Evans, DB, Hruban, RH (eds) Jones and Bartlet Publishers, Inc, pp 43–70

    Google Scholar 

  • Basu A, Woolard MD, Johnson CL (2001) Involvement of protein kinase C-delta in DNA damage-induced apoptosis. Cell Death Differ 8:899–908

    PubMed  CAS  Google Scholar 

  • Beger HG, Buchler MW, Friess H (1994) Surgical results and indications for adjuvant measures in pancreatic cancer. Chirurg 65:246–252

    PubMed  CAS  Google Scholar 

  • Bernstorff WV, Glickman JN, Odze RD, Farraye FA, Joo HG, Goedegebuure PS, Eberlein TJ (2002) Fas (CD95/APO-1) and Fas ligand expression in normal pancreas and pancreatic tumors. Implications for immune privilege and immune escape. Cancer 94:2552–2560

    PubMed  Google Scholar 

  • Bhanot U, Heydrich R, Möller P, Hasel C (2006) Survivin expression in pancreatic intraepithelial neoplasia (PanIN): steady increase along the developmental stages of pancreatic ductal adenocarcinoma. Am J Surg Pathol 30(6):754–9

    Google Scholar 

  • Birnbaum MJ, Clem RJ, Miller LK (1994) An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J Virol 68:2521–2528

    PubMed  CAS  Google Scholar 

  • Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Perez de Castro I, Li C, Thompson CB, Cox AD, Philips MR (2006) PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol Cell 21:481–493

    PubMed  CAS  Google Scholar 

  • Boehle AS, Kurdow R, Boenicke L, Schniewind B, Faendrich F, Dohrmann P, Kalthoff H (2002) Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo. Langenbecks Arch Surg 387:234–239

    PubMed  Google Scholar 

  • Boros LG, Lee WN, Go VL (2002) A metabolic hypothesis of cell growth and death in pancreatic cancer. Pancreas 24:26–33

    PubMed  Google Scholar 

  • Boros LG, Lerner MR, Morgan DL, Taylor SL, Smith BJ, Postier RG, Brackett DJ (2005) [1,2-13C2]-D-glucose profiles of the serum, liver, pancreas, and DMBA-induced pancreatic tumors of rats. Pancreas 31:337–343

    PubMed  CAS  Google Scholar 

  • Bose C, Zhang H, Udupa KB, Chowdhury P (2005) Activation of p-ERK 1/2 by nicotine in pancreatic tumor cell line AR42J: Effects on proliferation and secretion. Am J Physiol 289:G296–G234

    Google Scholar 

  • Bruns CJ, Harbison MT, Davis DW, Portera CA, Tsan R, McConkey DJ, Evans DB, Abbruzzese JL, Hicklin DJ, Radinsky R (2000) Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 6:1936–1948

    PubMed  CAS  Google Scholar 

  • Buchsbaum DJ, Bonner JA, Grizzle WE, Stackhouse MA, Carpenter M, Hicklin DJ, Bohlen P, Raisch KP (2002) Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys 54:1180–1193

    PubMed  CAS  Google Scholar 

  • Burgering B, Coffer P (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602

    PubMed  CAS  Google Scholar 

  • Campani D, Esposito I, Boggi U, Cecchetti D, Menicagli M, De Negri F, Colizzi L, Del Chiaro M, Mosca F, Fornaciari G, Bevilacqua G (2001) Bcl-2 expression in pancreas development and pancreatic cancer progression. J Pathol 194:444–450

    PubMed  CAS  Google Scholar 

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321

    PubMed  CAS  Google Scholar 

  • Cascinu S, Verdecchia L, Valeri N, Berardi R, Scartozzi M (2006) New target therapies in advanced pancreatic cancer. Ann Oncol 17:v148–52

    PubMed  Google Scholar 

  • Chi HB, Yang X, Kingsley PD, O’Keefe RJ, Puzas JE, Rosier RN, Shears SB, Reynolds PR (2000) Targeted deletion of minpp1 provides new insight into the activity of multiple inositol polyphosphate phosphatase in vivo. Mol Cell Biol 20:6496–6507

    PubMed  CAS  Google Scholar 

  • Chowdhury P, Bose C, Udupa KB (2007) Nicotine induced proliferation of isolated rat pancreatic acinar cells: effect on cell signaling and function. Cell Prolif 40:125–141

    PubMed  CAS  Google Scholar 

  • Chowdhury P, Walker A (2008) A cell based approach to study changes in the pancreas following nicotine exposure in an animal model of injury. Langenbecks Arch Surg 393(4):547-555

    PubMed  Google Scholar 

  • Coppola D (2000) Molecular prognostic markers in pancreatic cancer. Cancer Control 7:421–427

    PubMed  CAS  Google Scholar 

  • Craxton A, Ali N, Shears SB (1995) Comparison of the activities of a multiple inositol polyphosphate phosphatase obtained from several sources: a search for heterogeneity in this enzyme. J Biol Chem 305:491–498

    CAS  Google Scholar 

  • Craxton A, Caffrey JJ, Burkhart W, Safrany ST, Shears SB (1997) Molecular cloning and expression of a rat hepatic multiple inositol polyphosphate phosphatase. Biochem J 328:75–81

    PubMed  CAS  Google Scholar 

  • Cuendet M, Pezzuto JM (2000) The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. Drug Metabol Drug Interact 17:109–157

    PubMed  CAS  Google Scholar 

  • Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    PubMed  CAS  Google Scholar 

  • Denault JB, Salvesen GS (2002) Caspases: keys in the ignition of cell death. Chem Rev 102:4489–4500

    PubMed  CAS  Google Scholar 

  • Deveraux QL, Reed JC (1999) IAP family proteins – suppressors of apoptosis. Genes Dev 13:239–252

    PubMed  CAS  Google Scholar 

  • Deveraux QL, Schendel SL, Reed JC (2001) Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families. Cardiol Clin 19:57–74

    PubMed  CAS  Google Scholar 

  • Diallo JS, Péant B, Lessard L, Delvoye N, Page CL, Mes-Masson A-M, Saad F (2006) An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell lines. Prostate 66:1245–1256

    PubMed  CAS  Google Scholar 

  • Dong ML, Ding XZ, Adrian TE (2004) Red oil A5 inhibits proliferation and induces apoptosis in pancreatic cancer cells. World J Gastroenterol 10:105–111

    PubMed  CAS  Google Scholar 

  • Dong ML, Zhu YC, Hopkins JV (2003) Oil A induces apoptosis of pancreatic cancer cells via caspase activation, redistribution of cell cycle and GADD expression. World J Gastroenterol 9:2745–2750

    PubMed  Google Scholar 

  • Dorsey M, Benghuzzi H, Tucci M, Cason Z (2005) Growth and cell viability of estradiol and IP-6 treated Hep-2 laryngeal carcinoma cells. Biomed Sci Instrum 41:205–210

    PubMed  CAS  Google Scholar 

  • Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10(2):262–7

    PubMed  CAS  Google Scholar 

  • Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383–424

    PubMed  CAS  Google Scholar 

  • Elliott J, Scarpello JH, Morgan NG (2001) Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic beta-cell line, RINm5F.Br J Pharmacol 132:119–26

    Google Scholar 

  • Elnemr A, Ohta T, Yachie A, Kayahara M, Kitagawa H, Fujimura T, Ninomiya I, Fushida S, Nishimura GI, Shimizu K, Miwa K (2001) Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway. Int J Oncol 18:311–316

    PubMed  CAS  Google Scholar 

  • Elnemr A, Ohta T, Yachie A, Kayahara M, Kitagawa H, Ninomiya I, Fushida S, Fujimura T, Nishimura G, Shimizu K, Miwa K (2001a) Human pancreatic cancer cells express non-functional Fas receptors and counterattack lymphocytes by expressing Fas ligand; a potential mechanism for immune escape. Int J Oncol 8:33–39

    Google Scholar 

  • Evans JD, Cornford PA, Dodson A, Greenhalf W, Foster CS, Neoptolemos JP (2001) Detailed tissue expression of bcl-2, bax, bak and bcl-x in the normal human pancreas and in chronic pancreatitis, ampullary and pancreatic ductal adenocarcinomas. Pancreatology 1:254–262

    PubMed  CAS  Google Scholar 

  • Ferry S, Matsuda M, Yoshida H, Hirata M (2002) Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkappaB-mediated cell survival pathway. Carcinogenesis 23(12):2031–41

    PubMed  CAS  Google Scholar 

  • Food Nutrition Physical Activity and the Prevention of Cancer: A Global Perspective. (2007) In: AICR/WCRF. AICR, Washington DC

    Google Scholar 

  • Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88:435–437

    PubMed  CAS  Google Scholar 

  • Fuentes-Prior P, Salvesen GS (2004) The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 384:201–232

    PubMed  CAS  Google Scholar 

  • Ghadirian P, Lynch HT, Krewski D (2003) Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev 27:87–93

    PubMed  CAS  Google Scholar 

  • Ghaneh P, Costello E, Neoptolemos JP (2000) Biology and management of pancreatic cancer. Gut 56:1134–1152

    Google Scholar 

  • Giagkousiklidis S, Vogler M, Westhoff MA, Kasperczyk H, Debatin KM, Fulda S (2005) Sensitization for gamma-irradiation-induced apoptosis by second mitochondria-derived activator of caspase. Cancer Res 65:10502–10513

    PubMed  CAS  Google Scholar 

  • Gimm O, Chi H, Dahia P.L.M, Perren A, Hinze R, Komminoth P, Dralle H, Reynolds PR, Eng C (2001) Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas. J Clin Endocrinol Metab 86:1801–1805

    PubMed  CAS  Google Scholar 

  • Giovannucci E, Michaud D (2007) The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132:2208–2225

    PubMed  CAS  Google Scholar 

  • Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312

    PubMed  CAS  Google Scholar 

  • Hager JH, Hanahan D (1999) Tumor cells utilize multiple pathways to down-modulate apoptosis. Lessons from a mouse model of islet cell carcinogenesis. Ann N Y Acad Sci 887:150–163

    PubMed  CAS  Google Scholar 

  • He MX, Meng LX, Tang Y, Li JS, Tian BL, Hu WM, Huang X, Liu ZR, Zhang, ZD (2006) The experiment study on RNAi inhibiting the expression of survivin and inducing the apoptosis of pancreatic cancer cells. Sichuan Da Xue Xue Bao Yi Xue Ban 37:520–524

    PubMed  CAS  Google Scholar 

  • Hine RJ, Srivastava S, Milner JA, Ross SA (2003) Nutritional links to plausible mechanisms underlying pancreatic cancer: a conference report. Pancreas 27356–27366

    Google Scholar 

  • Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H, Ungefroren H (2000) Bcl-XL protects pancreatic adenocarcinoma cells against CD95- and TRAIL-receptor-mediated apoptosis. Oncogene 19:5477–5486

    PubMed  CAS  Google Scholar 

  • Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL (1993) K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143:545–554

    Google Scholar 

  • Hu Y, Benedict MA, Wu D, Inohara N, Nunez G (1998) Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 95:4386–4391

    PubMed  CAS  Google Scholar 

  • Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2:277–288

    PubMed  CAS  Google Scholar 

  • Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243

    PubMed  CAS  Google Scholar 

  • Janeb M, Thompson LU (2000) Phytic acid in wheat bran affects colon morphology, cell differentiation and apoptosis. Carcinogenesis 21:1547–1552

    Google Scholar 

  • Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM (2005) Fasting serum glucose level and cancer risk in Korean men and women. Jama 293:194–202

    PubMed  CAS  Google Scholar 

  • Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-García A, Leonardo E, Wennström S, von Kobbe C, Toran JL, R-Borlado L, Calvo V, Copin SG, Albar JP, Gaspar ML, Diez E, Marcos MA, Downward J, Martinez-A C, Mérida I, Carrera AC (1998) Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J 17:743–753

    Google Scholar 

  • Jones RG, Parsons M, Bonnard M, Chan VS, Yeh WC, Woodgett JR, Ohashi PS (2000) Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo. J Exp Med 191:1721–1734

    PubMed  CAS  Google Scholar 

  • Jones RG, Saibil SD, Pun JM, Elford AR, Bonnard M, Pellegrini M, Arya S, Parsons ME, Krawczyk CM, Gerondakis S, Yeh WC, Woodgett JR, Boothby MR, Ohashi PS (2005) NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo. J Immunol 175:3790–3799

    PubMed  CAS  Google Scholar 

  • Kami K, Doi R, Koizumi M, Toyoda E, Mori T, Ito D, Fujimoto K, Wada M, Miyatake S, Imamura M (2004) Survivin expression is a prognostic marker in pancreatic cancer patients. Surgery 136:443–448

    PubMed  Google Scholar 

  • Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC (2001) Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J Biol Chem 276:31099–31104

    PubMed  CAS  Google Scholar 

  • Kelekar A, Thompson CB (1998) Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 8:324–330

    PubMed  CAS  Google Scholar 

  • Kennedy SG, Wagner AJ, Conzen SD, Jordán J, Bellacosa A, Tsichlis PN (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11(6):701–13

    Google Scholar 

  • Klippel A, Escobado MA, Wachowicz MS, Apell G, Brown TW, Giedlin MA, Kavanaugh WM, Williams LT (1998) Activation of phosphatidylinositol 3-kinase is sufficient for cell cycle entry and promotes cellular changes characteristic of oncogenic transformation. Mol Cell Biol 18:5699–5711

    PubMed  CAS  Google Scholar 

  • Koopmann J, Rosenzweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo C, Chan DW, Breit SN, Goggins M (2006) Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19-9. Clin Cancer Res 2:442–446

    Google Scholar 

  • Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, Beger HG. (1992) Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90:1352–1360

    PubMed  CAS  Google Scholar 

  • Kornmann M, Ishiwata T, Kleeff J, Beger HG, Korc M (2000) Fas and Fas-ligand expression in human pancreatic cancer. Ann Surg 231:368–379

    PubMed  CAS  Google Scholar 

  • Korsmeyer SJ (1992) Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80:879–886

    PubMed  CAS  Google Scholar 

  • Krueger A, Baumann S, Krammer PH, Kirchhoff S (2001) FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 21:8247–8254

    PubMed  CAS  Google Scholar 

  • Laychock SG, Sessanna SM, Lin MH, Mastrandrea LD (2006) Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells. Endocrinology 147:4705–4712

    PubMed  CAS  Google Scholar 

  • Li X, Ding X, Adrian TE (2003) Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. Pancreas 27:174–179

    PubMed  CAS  Google Scholar 

  • Li Y, Ahmed F, Ali S, Philip PA, Kucuk O, Sarkar FH (2005) Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res 65:6934–6934

    PubMed  CAS  Google Scholar 

  • Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio, PC, Altieri DC. (1998) Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396:580–584

    PubMed  CAS  Google Scholar 

  • Liang Z, Wei S, Guan J, Luo Y, Gao J, Zhu H, Wu S, Liu T (2005) DNAzyme-mediated cleavage of survivin mRNA and inhibition of the growth of PANC-1 cells. J Gastroenterol Hepatol 20:1595–1602

    PubMed  CAS  Google Scholar 

  • Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine NR (2007) Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer 120:2344–2352

    PubMed  CAS  Google Scholar 

  • Lowenfels AB, Maisonneuve P (2005) Risk factors for pancreatic cancer. J Cell Biochem 95:649–656

    PubMed  CAS  Google Scholar 

  • Loweth AC, Williams GT, Scarpello JH, Morgan NG (1996) Heterotrimeric G-proteins are implicated in the regulation of apoptosis in pancreatic beta-cells. Exp Cell Res 229:69–76

    PubMed  CAS  Google Scholar 

  • Loweth AC, Williams GT, Scarpello JH, Morgan NG (1997) Evidence for the involvement of cGMP and protein kinase G in nitric oxide-induced apoptosis in the pancreatic B-cell line, HIT-T15. FEBS Lett 400:285–288

    PubMed  CAS  Google Scholar 

  • Lu X, Xu T, Qian J, Wen X, Wu D (2002) Detecting K-ras and p53 gene mutation from stool and pancreatic juice for diagnosis of early pancreatic cancer. Chin Med J (Engl) 115:1632–1636

    CAS  Google Scholar 

  • Luo HR, Huang YE, Chen JC, Saiardi A, Iijima M, Ye K, Huang Y, Nagata E, Devreotes P, Snyder SH (2003) Inositol Pyrophosphates Mediate Chemotaxis in Dictyostelium via Pleckstrin Homology Domain-PtdIns(3,4,5)P3 Interactions. Cell 114:559–572

    Google Scholar 

  • Maffucci T, Piccolo E, Cumashi A, Iezzi M, Riley AM, Saiardi A, Godage HY, Rossi C, Broggini M, Iacobelli S, Potter BVL, Innocenti P, Falasca M (2005) Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway by Inositol Pentakisphosphate Results in Antiangiogenic and Antitumor Effects. Cancer Res 65:8339–8349

    PubMed  CAS  Google Scholar 

  • Martinou JC, Green DR. (2001) Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2:63–67

    PubMed  CAS  Google Scholar 

  • Masui T, Hosotani R, Ito D, Kami K, Koizumi M, Mori T, Toyoda E, Nakajima S, Miyamoto, Y, Fujimoto K, Doi R (2006) Bcl-XL antisense oligonucleotides coupled with antennapedia enhances radiation-induced apoptosis in pancreatic cancer. Surgery 140:149–160

    PubMed  Google Scholar 

  • Matsuzaki H, Schmied BM, Ulrich A, Standop J, Schneider MB, Batra SK, Picha KS, Pour PM (2001) Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and actinomycin D induces apoptosis even in TRAIL-resistant human pancreatic cancer cells. Clin Cancer Res 7:407–414

    PubMed  CAS  Google Scholar 

  • Menniti FS, Miller RN, Putney JW Jr, Shears SB (1993) Turnover of inositol polyphosphate pyrophosphates in pancreatoma cells. J Biol Chem 268:3850–3856

    PubMed  CAS  Google Scholar 

  • Michaud DS, Liu S, Giovannucci E, Willett WC, Colditz GA, Fuchs CS (2002) Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study. J Natl Cancer Inst 94:1293–1300

    PubMed  CAS  Google Scholar 

  • Mimeault M, Brand RE, Sasson AA, Batra SK (2005) Recent advances on the molecular mechanisms involved in pancreatic cancer progression and therapies. Pancreas 31:301–316

    PubMed  CAS  Google Scholar 

  • Miyashita T, Reed JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81:151–157

    PubMed  CAS  Google Scholar 

  • Mori T, Doi R, Kida A, Nagai K, Kami, K, Ito D, Toyoda E, Kawaguchi Y, Uemoto S (2007) Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells. J Surg Res 142:281–286

    PubMed  CAS  Google Scholar 

  • Mori T, Doi R, Toyoda E, Koizumi M, Ito D, Kami K, Kida A, Masui T, Kawaguchi Y, Fujimoto K (2005) Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer. Surgery 138:71–77

    PubMed  Google Scholar 

  • Morrison BH, Bauer J.A, Kalvakolanu DV, Lindner DJ (2001) Inositol hexakisphosphate kinase-2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells. J Biol Chem 276:24965–24970

    PubMed  CAS  Google Scholar 

  • Moskaluk CA, Hruban RH, Kern SE (1997) p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57:2140–2143

    PubMed  CAS  Google Scholar 

  • Mouria M, Gukovskaya AS, Jung Y, Buechler P, Hines OJ, Reber HA, Pandol SJ (2002) Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis. Int J Cancer 98:761–769

    PubMed  CAS  Google Scholar 

  • Nagata E, Luo HR, Saiardi A, Bae B II, Suzuki N, Snyder SH (2005) Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. J Biol Chem 280:1634–1640

    PubMed  CAS  Google Scholar 

  • Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Buchler MW (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200–1210

    PubMed  CAS  Google Scholar 

  • Newman RA, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, Johansen M, Yang P (2007) Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther 6:354–364

    PubMed  CAS  Google Scholar 

  • Ng SS, Tsao MS, Chow S, Hedle, DW (2000) Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 60:5451–5455

    PubMed  CAS  Google Scholar 

  • Ng SS, Tsao MS., Nicklee T, Hedley DW (2001) Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res 7:3269–3275

    PubMed  CAS  Google Scholar 

  • Ng SS, Tsao MS, Nicklee T, Hedley DW (2002) Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Ther 1:777–783

    PubMed  CAS  Google Scholar 

  • Nothlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN (2007) Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr 86:1495–1501

    PubMed  CAS  Google Scholar 

  • Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592–603

    PubMed  CAS  Google Scholar 

  • Okhrimenko H, Lu W, Xiang C, Hamburger C, Kazimirsky G, Brodie C (2005) Protein kinase C-ε regulates the apoptosis and survival of glioma cells. Cancer Res 65:7301–7309

    PubMed  CAS  Google Scholar 

  • Ozaki S, DeWald DB, Shope JC, Chen J, Prestwich GD (2000) Intracellular delivery of phosphoinositides and inositol phosphates using polyamine carriers. PNAS 97:11286–11291

    PubMed  CAS  Google Scholar 

  • Park YJ, Wen J, Bang S, Park SW, Song SY (2006) [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Med J 47:688–697

    PubMed  CAS  Google Scholar 

  • Parker SL, Tong T, Bolden S, Wingo PA (1997) Cancer statistics, 1997. CA Cancer J Clin 47:5–27

    PubMed  CAS  Google Scholar 

  • Patel AV, McCullough ML, Pavluck AL, Jacobs EJ, Thun MJ, Calle EE (2007) Glycemic load, glycemic index, and carbohydrate intake in relation to pancreatic cancer risk in a large US cohort. Cancer Causes Control 18:287–294

    PubMed  Google Scholar 

  • Pesesse X, Choi K, Zhang T, Shears SB (2004) Signaling by higher Inositolpolyphosphates: Hyperosmotic stress acutely and selectively activates synthesis of bis-diphosphoinositol tetrakisphosphate (“InsP8”). J Biol Chem 279:43378–43381

    PubMed  CAS  Google Scholar 

  • Pettersson F, Dalgleish AG, Bissonnette RP, Colston KW (2002) Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax. Br J Cancer 87:555–561

    PubMed  CAS  Google Scholar 

  • Piccolo E, Vignati S, Maffucci T, Innominato PF, Riley AM, Potter BV, Pandolfi PP, Broggini M, Iacobelli S, Innocenti P, Falasca M (2004) Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Oncogene 23:1754–1765

    PubMed  CAS  Google Scholar 

  • Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 96:1563–1568

    PubMed  CAS  Google Scholar 

  • Pop C, Timmer J, Sperandio S, Salvesen, GS (2006) The apoptosome activates caspase-9 by dimerization. Mol Cell 22:269–275

    PubMed  CAS  Google Scholar 

  • Putt KS, Chen GW, Pearson JM, Sandhorst JS, Hoagland MS, Kwon JT, Hwang SK, Jin H, Churchwell M I, Cho MH, Doerge DR, Helferich WG, Hergenrother PJ (2006) Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat Chem Biol 2:543–550

    PubMed  CAS  Google Scholar 

  • Qanungo S, Das M, Haldar S, Basu A (2005) Epigallocatechin-3-gallate induces mitochondrial membrane depolarization and caspase-dependent apoptosis in pancreatic cancer cells. Carcinogenesis 26:958–967

    PubMed  CAS  Google Scholar 

  • Rathmell JC, Thompson CB (1999) The central effectors of cell death in the immune system. Annu Rev Immunol 17:781–828

    PubMed  CAS  Google Scholar 

  • Razzini G, Berrie CP, Vignati S, Broggini M, Mascetta G, Brancaccio A, Falasca M (2000) Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines. FASEB J. 14:179–1187

    Google Scholar 

  • Reed JC, Green DR (2002) Remodeling for demolition: changes in mitochondrial ultrastructure during apoptosis. Mol Cell 9:1–3

    PubMed  CAS  Google Scholar 

  • Refsnes M, Kersten H, Schwarze PE, Lag M (2002) Involvement of Protein Kinase C in Fluoride-Induced Apoptosis in Different Types of Lung Cells. Ann NY Acad Sci 973:218–220

    PubMed  CAS  Google Scholar 

  • Reszka E, Wasowicz W, Gromadzinska J (2006) Genetic polymorphism of xenobiotic metabolising enzymes, diet and cancer susceptibility. Br J Nutr 96:609–619

    PubMed  CAS  Google Scholar 

  • Retzer-Lidl M, Schmid RM, Schneider G (2007) Inhibition of CDK4 impairs proliferation of pancreatic cancer cells and sensitizes towards TRAIL-induced apoptosis via downregulation of survivin. Int J Cancer 121:66–75

    PubMed  CAS  Google Scholar 

  • Rizvi I, Riggs DR, Jackson BJ, Ng A, Cunningham C, McFadden DW (2006) Inositol Hexaphosphate (IP6) inhibits cellular proliferation in melanoma. J Surg Res 130:192–192

    Google Scholar 

  • Roy S, Bayly CI, Gareau Y, Houtzager VM, Kargman S, Keen SL, Rowland K, Seiden IM, Thornberry NA, Nicholson DW (2001) Maintenance of caspase-3 proenzyme dormancy by an intrinsic “safety catch” regulatory tripeptide. Proc Natl Acad Sci USA 98:6132–6137

    PubMed  CAS  Google Scholar 

  • Safrany ST, Shears SB (1998) Turnover of bis-diphosphoinositol tetrakisphosphate in a smooth muscle cell line is regulated by beta2-adrenergic receptors through a cAMP-mediated, A-kinase-independent mechanism. Eur Mol Biol Organ J 17:1710–1716

    CAS  Google Scholar 

  • Salabat MR, Ding XZ, Flesche JB, Ujiki MB, Robin TP, Talamonti MS, Bell RH Jr, Adrian TE (2006) On the mechanisms of 12-O-tetradecanoylphorbol-13-acetate-induced growth arrest in pancreatic cancer cells. Pancreas 33:148–155

    PubMed  CAS  Google Scholar 

  • Salek C, Benesova L, Zavoral M, Nosek V, Kasperova L, Ryska M, Strnad R, Traboulsi E, Minarik M (2007) Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer. World J Gastroenterol 13:3714–20

    PubMed  CAS  Google Scholar 

  • Salvesen GS, Renatus M (2002) Apoptosome: the seven-spoked death machine. Dev Cell 2:256–257

    PubMed  CAS  Google Scholar 

  • Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF, Guillou PJ (2002) Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer 86:886–892

    PubMed  CAS  Google Scholar 

  • Sartorius U, Schmitz I, Krammer PH (2001) Molecular mechanisms of death-receptor-mediated apoptosis. Chembiochem 2:20–29

    PubMed  CAS  Google Scholar 

  • Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T (2001) Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 92:271–278

    PubMed  CAS  Google Scholar 

  • Satoh K, Kaneko K, Hirota M, Toyota T, Shimosegawa T (2000) The pattern of CPP32/caspase-3 expression reflects the biological behavior of the human pancreatic duct cell tumors. Pancreas 21:352–357

    PubMed  CAS  Google Scholar 

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. Embo J 17:1675–1687

    PubMed  CAS  Google Scholar 

  • Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H, Ungefroren H (2004) Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int J Cancer 109:182–188

    PubMed  CAS  Google Scholar 

  • Senderowicz AM, Johnson JR, Sridhara R, Zimmerman P, Justice R, Pazdur R (2007) Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. Oncology (Williston Park) 21:1696–1706

    Google Scholar 

  • Sethi G, Sung B, Aggarwal BB (2008) Nucleat factor-kappaB activation: From bench to bedside. Exp Biol Med 233:21–31

    CAS  Google Scholar 

  • Sharma G, Singh RP, Agarwal R (2003) Growth inhibitory and apoptotic effects of inositol hexaphosphate in transgenic adenocarcinoma of mouse prostate (TRAMP-C1) cells. Int J Oncol 23:1413–1418

    PubMed  CAS  Google Scholar 

  • Shayesteh L, Lu Y, Kuo W-L, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102

    PubMed  CAS  Google Scholar 

  • Shears SB, Ali N, Craxton A, Bembenek ME (1995) Synthesis and metabolism of bis-diphosphoinositol tetrakisphosphate in vitro and in vivo. J Biol Chem 270:10489–10497

    PubMed  CAS  Google Scholar 

  • Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, Jin F, Zheng W (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 13:190–196

    PubMed  CAS  Google Scholar 

  • Silverman DT (2001) Risk factors for pancreatic cancer: a case-control study based on direct interviews. Teratog Carcinog Mutagen 21:7–25

    PubMed  CAS  Google Scholar 

  • Singh RP, Agarwal C, Agarwal R (2003) Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis 24(3):555–63

    PubMed  CAS  Google Scholar 

  • Singh B, Murphy RF, Ding XZ, Roginsky AB, Bell RH Jr, Adrian TE (2007) On the role of transforming growth factor-beta in the growth inhibitory effects of retinoic acid in human pancreatic cancer cells. Mol Cancer 6:82

    PubMed  Google Scholar 

  • Singh RP, Sharma G, Mallikarjuna GU, Dhanalakshmi S, Agarwal C, Agarwal R (2004) In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: Induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor. Clin Cancer Res 10:244–250

    PubMed  CAS  Google Scholar 

  • Somasundar P, Riggs D, Jackson B, Cunningham C, Vona-Davis L, McFadden D (2005) Inositol Hexaphosphate (IP6): A novel treatment for pancreatic cancer. J Surg Res 126:199–203

    PubMed  CAS  Google Scholar 

  • Song Y, Manson JE, Buring JE, Sesso HD, Liu S (2005) Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. J Am Coll Nutr 24:376–384

    PubMed  CAS  Google Scholar 

  • Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH, Walczak H (2000) FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12:599–609

    PubMed  CAS  Google Scholar 

  • Srinivasan V, Sandhya N, Sampathkumar R, Farooq S, Mohan V, Balasubramanyam M (2007) Glutamine fructose-6-phosphate amidotransferase (GFAT) gene expression and activity in patients with type 2 diabetes: inter-relationships with hyperglycaemia and oxidative stress. Clin Biochem 40:952–957

    PubMed  CAS  Google Scholar 

  • Stephens LR, Jackson TR, Hawkins PT (1993) Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system? Biochim biophys Acta Mol Cell Res 1179:27–75

    Google Scholar 

  • Stolzenberg-Solomon RZ, Adams K, Leitzmann M, Schairer C, Michaud DS, Hollenbeck A, Schatzkin A, Silverman DT (2008) Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort. Am J Epidemiol 167:586–597

    PubMed  Google Scholar 

  • Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, Albanes D. (2006) A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 66:10213–10219

    PubMed  CAS  Google Scholar 

  • Stolzenberg-Solomon RZ, Graubard BL, Chari S, Limburg P, Taylor PR, Virtama J, Albanes D (2005) Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294:2872–8

    PubMed  CAS  Google Scholar 

  • Suda T, Takahashi T, Golstein P, Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75:1169–1178

    PubMed  CAS  Google Scholar 

  • Sun W, Wang W, Kim J, Keng P, Yang S, Zhang H, Liu C, Okunieff P, Zhang L (2008) Anti-cancer effect of resveratrol is associated with induction of apoptosis via a mitochondrial pathway alignment. Adv Exp Med Biol 614:179–186

    PubMed  Google Scholar 

  • Suzuki K, Islam KN, Kaneto H, Ookawara T, Taniguchi N (2000) The contribution of fructose and nitric oxide to oxidative stress in hamster islet tumor (HIT) cells through the inactivation of glutathione peroxidase. Electrophoresis 21:285–288

    PubMed  CAS  Google Scholar 

  • Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320

    PubMed  CAS  Google Scholar 

  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281(5381):1312–6

    PubMed  CAS  Google Scholar 

  • Timmer JC, Salvesen GS (2007) Caspase substrates. Cell Death Differ 14:66–72

    PubMed  CAS  Google Scholar 

  • Tong WG, Ding XZ, Talamonti MS, Bell RH, Adrian TE (2007) Leukotriene B4 receptor antagonist LY293111 induces S-phase cell cycle arrest and apoptosis in human pancreatic cancer cells. Anticancer Drugs 18:535–541

    PubMed  CAS  Google Scholar 

  • Tong WG, Ding XZ, Witt RC, Adrian TE (2002) Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol Cancer Ther 1:929–935

    PubMed  CAS  Google Scholar 

  • Trauzold A, Schmiedel S, Roder C, Tams C, Christgen M, Oestern S, Arlt A, Westphal S, Kapischke M, Ungefroren H, Kalthoff H (2003) Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells. Br J Cancer 89:1714–1721

    PubMed  CAS  Google Scholar 

  • Trauzold A, Siegmund D, Schniewind, B, Sipos B, Egberts J, Zorenkov D, Emme D, Roder C, Kalthoff H, Wajant H (2006) TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 25:7434–7439

    PubMed  CAS  Google Scholar 

  • Tsuji N, Asanuma K, Kobayashi D, Yagihashi A, Watanabe N (2005) Introduction of a survivin gene-specific small inhibitory RNA inhibits growth of pancreatic cancer cells. Anticancer Res 25:3967–3972

    PubMed  CAS  Google Scholar 

  • Turner PR, Mefford S, Christakos S, Nissenson RA (2000) Apoptosis mediated by activation of the G protein-coupled receptor for parathyroid hormone (PTH)/PTH-related protein (PTHrP). Mol Endocrinol 14:241–254

    PubMed  CAS  Google Scholar 

  • Ungefroren H, Kruse ML, Trauzold A, Roeschmann S, Roeder C, Arlt A, Henne-Bruns D, Kalthoff H (2001) FAP-1 in pancreatic cancer cells: functional and mechanistic studies on its inhibitory role in CD95-mediated apoptosis. J Cell Sci 114:2735–2746

    PubMed  CAS  Google Scholar 

  • Verbsky JW, Majerus PW (2005) Increased levels of inositol hexakisphosphate (InsP6) protect HEK293 cells from TNFa and Fas induced apoptosis. J Biol Chem 280:29263–29268

    PubMed  CAS  Google Scholar 

  • Vogler M, Durr K, Jovanovic M, Debatin KM, Fulda S (2007) Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells. Oncogene 26:248–257

    PubMed  CAS  Google Scholar 

  • Vogler M, Giagkousiklidis S, Genze F, Gschwend JE, Debatin KM, Fulda S (2005) Inhibition of clonogenic tumor growth: a novel function of Smac contributing to its antitumor activity. Oncogene 24:7190–7202

    PubMed  CAS  Google Scholar 

  • von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7:925s–932s

    Google Scholar 

  • Vucenik I, Shamsuddin AM (2003) Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic. J Nutr 133(11 Suppl 1):3778S–3784S

    PubMed  CAS  Google Scholar 

  • Vucenik I, Ramakrishna G, Tantivejkul K, Anderson LM, Ramljak D (2005) Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCδ-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Res Treat 91:35–45

    PubMed  CAS  Google Scholar 

  • Vucic D, Fairbrother WJ (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13:5995–6000

    PubMed  CAS  Google Scholar 

  • Wang P, Zhang J, Bellail A, Jiang W, Hugh J, Kneteman NM, Hao C (2007) Inhibition of RIP and c-FLIP enhances TRAIL-induced apoptosis in pancreatic cancer cells. Cell Signal 19:2237–2246

    PubMed  CAS  Google Scholar 

  • Weglarz L, Parfiniewicz B, Orchel A, Dzierzewicz Z (2006) Anti-proliferative effects of inositol hexaphosphate and verapamil on human colon cancer Caco-2 and HT-29 cells. Acta Pol Pharm 63:443–445

    PubMed  CAS  Google Scholar 

  • Westphal S, Kalthoff H (2003) Apoptosis: targets in pancreatic cancer. Mol Cancer 2:6

    PubMed  Google Scholar 

  • Wilson M.P, Sun Y, Cao L, Majerus PW (2001) Inositol 1,3,4-Trisphosphate 5/6-Kinase Is a Protein Kinase That Phosphorylates the Transcription Factors c-Jun and ATF-2. J Biol Chem 276:40998–41004

    PubMed  CAS  Google Scholar 

  • Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC (2006) Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 55:1294–1298

    PubMed  CAS  Google Scholar 

  • Xu ZW, Friess H, Buchler MW, Solioz M (2002) Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. Cancer Chemother Pharmacol 49:504–510

    PubMed  CAS  Google Scholar 

  • Xu G, Wu K, Wang XP, Zhao S (2005) Enhancing effects of celecoxib on the growth inhibition of pancreatic carcinoma by gemcitabine treatment. Zhonghua Yi Xue Za Zhi 85:986–91

    PubMed  CAS  Google Scholar 

  • Yeh JJ, Der CJ (2007) Targeting signal transduction in pancreatic cancer treatment. Expert Opin Ther Targets 11:673–694

    PubMed  CAS  Google Scholar 

  • Yip-Achneider MT, Wu H, Ralstin M, Yannoutsos C, Crooks PA, Neelakantan S, Noble S, Nakshatri H, Sweeney CJ, Schmidt CM (2007) Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo. Mol Cancer Ther 6:1736–44

    Google Scholar 

  • Yip TT, Lomas L (2002) SELDI ProteinChip array in oncoproteomic research. Technol Cancer Res Treat 1:273–280

    PubMed  CAS  Google Scholar 

  • Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz R (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75:641–652

    PubMed  CAS  Google Scholar 

  • Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2:67–71

    PubMed  CAS  Google Scholar 

  • Zhao S, Ammanamanchi S, Brattain M, Cao L, Thangasamy A, Wang J, Freeman JW (2008) Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase dependent motility and invasion of pancreatic cancer cells. J Biol Chem 283(17):11293–301

    PubMed  CAS  Google Scholar 

  • Zhu K, Qin H, Cha SC, Neelapu SS, Overwijk W, Lizee GA, Abbruzzese JL, Hwu P, Radvanyi L, Kwak LW, Chang DZ (2007) Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models. Vaccine 25:7955–7961

    PubMed  CAS  Google Scholar 

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Ali, N., MacLeod, S., Hine, R.J., Chowdhury, P. (2009). Cellular Signaling Mechanisms in Pancreatic Apoptosis. In: Chen, G.G., Lai, P.B. (eds) Apoptosis in Carcinogenesis and Chemotherapy. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9597-9_13

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