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Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21CIP1/WAF1 induction rather than AKT inhibition

Abstract

Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 μ M) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of ΔΨm), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB±LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21CIP1/WAF1; moreover, enforced expression of p21CIP1/WAF1 significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21CIP1/WAF1 induction.

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References

  • Alessi DR and Cohen P . (1998). Curr. Opin. Genet. Dev., 8, 55–62.

  • Asada M, Yamada, Fukumuro K and Mizutani S . (1998). Leukemia, 12, 1944–1950.

  • Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K and Mizutani S . (1999). EMBO J., 18, 1223–1234.

  • Balmanno K and Cook J . (1999). Oncogene, 18, 3085–3097.

  • Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM and Anderson DW . (2001). Proc. Natl. Acad. Sci. USA, 98, 13681–13686.

  • Burgess AJ, Pavey S, Warrener R, Hunter LJ, Piva TJ, Musgrove EA, Saunders N, Parsons PG and Gabrielli BG . (2001). Mol. Pharmacol., 60, 828–837.

  • Byrd JC, Shinn C, Ravi R, Willis CR, Waselenko JK, Flinn IW, Dawson NA and Grever MR . (1999). Blood, 94, 1401–1408.

  • Cartee L, Wang Z, Decker RH, Chellappan SP, Fusaro G, Hirsch KG, Sankala HM, Dent P and Grant S . (2001). Cancer Res., 61, 2583–2591.

  • Cataldi A, Di Pietro R, Centurione L, Grilli A, Cutroneo G and Miscia S . (2000). Cell Signal., 12, 667–672.

  • Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J and Staels B . (1998). J. Biol .Chem., 273, 25573–25580.

  • Chou TC and Talalay P . (1984). Adv. Enzyme Regul., 22, 27–55.

  • Das D, Pintucci G and Stern A . (2000). FEBS Lett., 472, 50–52.

  • Deveraux QL and Reed JC . (1999). Genes Dev., 13, 239–252.

  • Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D and Koeffler HP . (1998). Proc. Natl. Acad. Sci. USA, 95, 8806–8811.

  • Fan M and Chambers TC . (2001). Drug Resist. Updat., 4, 253–267.

  • Fang G, Kim CN, Perkins CL, Ramadevi N, Winton E, Wittmann S and Bhalla KN . (2000). Blood, 96, 2246–2253.

  • Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K and Sessa WC . (2001). J. Biol. Chem., 276, 30359–30365.

  • Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P and Korsmeyer SJ . (1999). J. Biol. Chem., 274, 1156–1163.

  • Grunstein M . (1997). Nature, 389, 349–352.

  • Gum JR, Kam WK, Byrd JC, Hicks JW, Sleisenger MH and Kim YS . (1987). J. Biol. Chem., 262, 1092–1097.

  • Hawes BE, Luttrell LM, van Biesen T and Lefkowitz RJ . (1996). J. Biol. Chem., 271, 12133–12136.

  • King WG, Mattaliano MD, Chan TO, Tsichlis PN and Brugge JS . (1997). Mol. Cell. Biol., 17, 4406–4418.

  • Kirsch DG, Doseff A, Chau BN, Lim DS, Souza-Pinto NC, Hansford R, Kastan MB, Lazebnik YA and Hardwick JM . (1999). J. Biol. Chem., 274, 21155–21161.

  • Kivinen L, Tsubari M, Haapajarvi T, Datto MB, Wang XF and Laiho M . (1999). Oncogene, 18, 6252–6261.

  • Kubota Y, Angelotti T, Niederfellner G, Herbst R and Ullrich A . (1998). Cell Growth Differ., 9, 247–256.

  • Kubota Y, Tanaka T, Kitanaka A, Ohnishi H, Okutani Y, Waki M, Ishida T and Kamano H . (2001). EMBO J., 20, 5666–5677.

  • Lee BI, Park SH, Kim JW, Sausville EA, Kim HT, Nakanishi O, Trepel JB and Kim SJ . (2001). Cancer Res., 61, 931–934.

  • Lewandowski D, Linassier C, Iochmann S, Degenne M, Domenech J, Colombat P, Binet C and Herault O . (2002). Br. J. Haematol., 118, 535–544.

  • Marks PA, Richon VM and Rifkind RA . (2000). J. Natl. Cancer Inst., 92, 1210–1216.

  • Marks P, Rifkind RA, Richon VM, Breslow R, Miller T and Kelly WK . (2001). Nat. Rev. Cancer., 1, 194–202.

  • Martin SJ, Bradley JG and Cotter TG . (1990). Clin. Exp. Immunol., 79, 448–453.

  • Miranda MB, McGuire TF and Johnson DE . (2002). Leukemia, 16, 683–692.

  • Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC and Testa JR . (2000). Cancer Res., 60, 5390–5394.

  • Moulding DA, Giles RV, Spiller DG, White MR, Tidd DM and Edwards SW . (2000). Blood, 96, 1756–1763.

  • Murga C, Zohar M, Teramoto H and Gutkind JS . (2002). Oncogene, 21, 207–216.

  • Nakashio A, Fujita N, Rokudai S, Sato S and Tsuruo T . (2000). Cancer Res., 60, 5303–5309.

  • Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y and Kraft AS . (2001). J. Biol. Chem., 276, 10767–10774.

  • Nicholson KM and Anderson NG . (2002). Cell Signal., 14, 381–395.

  • Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M and Lin J . (2000). Anticancer Res., 20, 407–416.

  • Park J, Leong ML, Buse P, Maiyar AC, Firestone GL and Hemmings BA . (1999). EMBO J., 18, 3024–3033.

  • Park SJ, Kang SY, Kim NS and Kim HM . (2002). Immunopharmacol. Immunotoxicol., 24, 211–226.

  • Rahmani M, Dai Y and Grant S . (2002). Exp. Cell Res., 277, 31–47.

  • Rane SG, Mangan JK, Amanullah A, Wong BC, Vora RK, Liebermann DA, Hoffman B, Grana X and Reddy EP . (2002). Blood, 100, 2753–2762.

  • Romashkova JA and Makarov SS . (1999). Nature, 401, 86–90.

  • Rosato RR, Almenara JA, Cartee L, Betts V, Chellappan SP and Grant S . (2002). Mol. Cancer Ther., 1, 253–266.

  • Rosato RR, Wang Z, Gopalkrishnan RV, Fisher PB and Grant S . (2001). Int. J. Oncol, 19, 181–191.

  • Rossig L, Badorff C, Holzmann Y, Zeiher AM and Dimmeler S . (2002). J. Biol. Chem., 277, 9684–9689.

  • Sidhu JS, Liu F, Boyle SM and Omiecinski CJ . (2001). Mol. Pharmacol., 59, 1138–1146.

  • Sowa Y and Sakai T . (2000). Biofactors, 12, 283–287.

  • Stein RC . (2001). Endocr. Relat. Cancer, 8, 237–248.

  • Suzuki A, Tsutomi Y, Akahane K, Araki T and Miura M . (1998). Oncogene, 17, 931–939.

  • Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983–10985.

  • Vigushin DM and Coombes RC . (2002). Anticancer Drugs, 13, 1–13.

  • Vlahos CJ, Matter WF, Hui KY and Brown RF . (1994). J. Biol. Chem., 269, 5241–5248.

  • Vrana JA, Decker RH, Johnson CR, Wang Z, Jarvis WD, Richon VM, Ehinger M, Fisher PB and Grant S . (1999). Oncogene, 18, 7016–7025.

  • Wang, Li, Kim and and Evers . (2002). Clin. Cancer Res., 8, 1940–1947.

  • Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME . (1995). Science, 270, 1326–1331.

  • Young PR, McLaughlin MM, Kumar S, Kassis S, Doyle ML, McNulty D, Gallagher TF, Fisher S, McDonnell PC, Carr SA, Huddleston MJ, Seibel G, Porter TG, Livi GP, Adams JL and Lee JC . (1997). J. Biol. Chem., 272, 12116–12121.

  • Yu C, Rahmani M, Dai Y, Conrad D, Krystal G, Dent P and Grant S . (2003). Cancer Res., 63, 1822–1833.

  • Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA and Schrump DS . (2002). J. Natl. Cancer Inst., 94, 504–513.

  • Yusta B, Estall J and Drucker DJ . (2002). J. Biol. Chem., 277, 24896–24906.

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Acknowledgements

This work was supported by awards CA 63753 and CA 93798 from the NIH, and Award 6045-03 from the Leukemia and Lymphoma Society of America.

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Correspondence to Steven Grant.

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Rahmani, M., Yu, C., Reese, E. et al. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21CIP1/WAF1 induction rather than AKT inhibition. Oncogene 22, 6231–6242 (2003). https://doi.org/10.1038/sj.onc.1206646

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