Skip to main content
SpringerLink
Log in

Caspase-dependent and -independent death pathways in cancer therapy

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

The majority of current anticancer therapies induce tumor cell death through the induction of apoptosis. Alterations in the apoptotic pathways may determine tumor resistance to these therapies. Activation of the proteolytic cascade involving caspase family members is a critical component of the execution of cell death in apoptotic cells. However, recent studies suggest that cell death can proceed in the absence of caspases. In this review we describe the role of caspase-dependent and -independent pathways as targets for anticancer treatment; better understanding of diverse modes of tumor cell death will help to avoid ineffective treatment and provide a molecular basis for the new strategies targeting caspase-independent death pathways in apoptosis-resistant forms of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997; 89: 1845–1853.

    Google Scholar 

  2. Sayers TJ, Brooks AD, Lee JK, et al. Molecular mechanisms of immune-mediated lysis of murine renal cancer: differential contributions of perforin-dependent versus Fas-mediated pathways in lysis by NK and T cells. J Immunol 1998; 161: 3957–3965.

    Google Scholar 

  3. Hirata H, Takahashi A, Kobayashi S, et al. Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med 1998; 187: 587–600.

    Google Scholar 

  4. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281: 1312–1316.

    Google Scholar 

  5. Kolenko V, Uzzo RG, Bukowski R, et al. Dead or dying: necrosis versus apoptosis in caspase-deficient human renal cell carcinoma. Cancer Res 1999; 59: 2838–2842.

    Google Scholar 

  6. Martinez-Lorenzo MJ, Gamen S, Etxeberria J, et al. Resistance to apoptosis correlates with a highly proliferative phenotype and loss of Fas and CPP32 (caspase-3) expression in human leukemia cells. Int J Cancer 1998; 75: 473–481.

    Google Scholar 

  7. Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K, Debatin KM. Cross-resistance of CD95–and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). Blood 1997; 90: 3118–3129.

    Google Scholar 

  8. Friesen C, Fulda S, Debatin KM. Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia 1997; 11: 1833–1841.

    Google Scholar 

  9. Fulda S, Los M, Friesen C, Debatin KM. Chemosensitivity of Apoptosis V. M. Kolenko et al. solid tumor cells in vitro is related to activation of the CD95 system. Int J Cancer 1998; 76: 105–114.

    Google Scholar 

  10. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17: 1675–1687.

    Google Scholar 

  11. Muller M, Strand S, Hug H, et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ ligand system and involves activation of wild-type p53. J Clin Invest 1997; 99: 403–413.

    Google Scholar 

  12. Clement MV, Hirpara JL, Chawdhury SH, Pervaiz S. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 1998; 92: 996–1002.

    Google Scholar 

  13. Tolomeo M, Dusonchet L, Meli M, et al. The CD95/CD95 ligand system is not the major effector in anticancer drugmediated apoptosis. Cell Death Differ 1998; 5: 735–742.

    Google Scholar 

  14. Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem. 1999; 274: 7987–7992.

    Google Scholar 

  15. Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K. Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 1999; 93: 3053–3063.

    Google Scholar 

  16. Ferrari D, Stepczynska A, Los M, Wesselborg S, Schulze-Osthoff K. Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during. J Exp Med. 1998; 188: 979–984.

    Google Scholar 

  17. Bantel H, Engels IH, Voelter W, Schulze-Osthoff K, Wesselborg S. Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis. Cancer Res 1999; 59: 2083–2090.

    Google Scholar 

  18. Hirsch T, Marchetti P, Susin SA, et al. The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 1997; 15: 1573–1581.

    Google Scholar 

  19. Reiter I, Krammer B, Schwamberger G. Cutting edge: differential effect of apoptotic versus necrotic tumor cells on macrophage antitumor activities. J Immunol 1999; 163: 1730–1732.

    Google Scholar 

  20. Arai H, Gordon D, Nabel EG, Nabel GJ. Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 1997; 94: 13862–13867.

    Google Scholar 

  21. Hedlund TE, Meech SJ, Srikanth S, et al. Adenovirus-mediated expression of Fas ligand induces apoptosis of human prostate cancer cells. Cell Death Differ 1999; 6: 175–182.

    Google Scholar 

  22. Keane MM, Ettenberg SA, Lowrey GA, Russell EK, Lipkowitz S. Fas expression and function in normal and malignant breast cell lines. Cancer Res 1996; 56: 4791–4798.

    Google Scholar 

  23. Koshiji M, Adachi Y, Sogo S, et al. Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma), resulting from down-modulation of Bcl-2 expression. Clin Exp Immunol 1998; 111: 211–218.

    Google Scholar 

  24. Muschen M, Warskulat U, Schmidt B, Schulz WA, Haussinger D. Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in human embryonal carcinoma cells by interferon gamma and all-trans retinoic acid. Biol Chem 1998; 379: 1083–1091.

    Google Scholar 

  25. Weller M, Schuster M, Pietsch T, Schabet M. CD95 ligandinduced apoptosis of human medulloblastoma cells. Cancer Lett 1998; 128: 121–126.

    Google Scholar 

  26. Roth W, Wagenknecht B, Dichgans J, Weller M. Interferonalpha enhances CD95L-induced apoptosis of human malignant glioma cells. J Neuroimmunol 1998; 87: 121–129.

    Google Scholar 

  27. Smyth MJ, Krasovskis E, Sutton VR, Johnstone RW. The drug efflux protein, P-glycoprotein, additionally protects drugresistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sci USA 1998; 95: 7024–7029.

    Google Scholar 

  28. Johnstone RW, Cretney E, Smyth MJ. P-glycoprotein protects leukemia cells against caspase-dependent, but not caspaseindependent, cell death. Blood 1999; 93: 1075–1085.

    Google Scholar 

  29. Bloem A, Lockhorst H. Bcl-2 antisense therapy in multiple myeloma. Pathol Biol 1999; 47: 216–220.

    Google Scholar 

  30. Tu Y, Renner S, Xu F, et al. BCL-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 1998; 58: 256–262.

    Google Scholar 

  31. McConkey DJ, Chandra J, Wright S, et al. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX. J Immunol 1996; 156: 2624–2630.

    Google Scholar 

  32. Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–969.

    Google Scholar 

  33. Piche A, Grim J, Rancourt C, Gomez-Navarro J, Reed JC, Curiel DT. Modulation of Bcl-2 protein levels by an intracellular anti-Bcl-2 single-chain antibody increases drug-induced cytotoxicity in the breast cancer cell line MCF-7. Cancer Res 1998; 58: 2134–2140.

    Google Scholar 

  34. Okuno S, Shimizu S, Ito T, et al. Bcl-2 prevents caspaseindependent cell death. J Biol Chem 1998; 273: 34272–34277.

    Google Scholar 

  35. Reed JC. Mechanisms of apoptosis avoidance in cancer. Curr Opin Oncol 1999; 11: 68–75.

    Google Scholar 

  36. Chi S, Kitanaka C, Noguchi K, et al. Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. Oncogene 1999; 18: 2281–2290.

    Google Scholar 

  37. Xiang J, Chao DT, Korsmeyer SJ. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci USA 1996; 93: 14559–14563.

    Google Scholar 

  38. Pinkoski MJ, Hobman M, Heibein JA, et al. Entry and trafficking of granzyme B in target cells during granzyme B-perforinmediated apoptosis. Blood 1998; 92: 1044–1054.

    Google Scholar 

  39. Beresford PJ, Xia Z, Greenberg AH, Lieberman J. Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation. Immunity 1999; 10: 585–594.

    Google Scholar 

  40. Sarin A, Williams MS, Alexander-Miller MA, Berzofsky JA, Zacharchuk CM, Henkart PA. Target cell lysis by CTL granule exocytosis is independent of ICE/Ced-3 family proteases. Immunity 1997; 6: 209–215.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology and Experimental Therapeutics Program, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    Vladimir M. Kolenko & Ronald Bukowski

  2. Department of Immunology and Department of Urology, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    Robert G. Uzzo

  3. Department of Immunology, Department of Urology and Experimental Therapeutics Program, The Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

    James H. Finke

Authors
  1. Vladimir M. Kolenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert G. Uzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald Bukowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James H. Finke
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kolenko, V.M., Uzzo, R.G., Bukowski, R. et al. Caspase-dependent and -independent death pathways in cancer therapy. Apoptosis 5, 17–20 (2000). https://doi.org/10.1023/A:1009677307458

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009677307458

Search

Navigation