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Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis

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Abstract

Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, can induce apoptosis, but the molecular mechanisms remain to be fully elucidated. We have recently reported that TG-induced apoptosis appears to involve the DR5-dependent apoptotic pathway that cross talks with the mitochondrial pathway via TG-induced Bid cleavage. In this study, we have utilized Bax-proficient and -deficient HCT116 human colon cancer cells to investigate the effect of Bax deficiency on TG-induced apoptosis and TG regulation of the DR5 and mitochondrial pathways. Our results indicate that Bax-deficient cells are less sensitive to undergo apoptosis following TG treatment. Our results further demonstrate that TG-induced apoptosis is coupled with DR5 upregulation and caspases 8 and 3 activation, as well as Bid cleavage in both Bax-proficient and -deficient cells, although caspase 3 activation was reduced in Bax-deficient cells. TG also promoted the release of cytochrome c into cytosol and caspase 9 activation in Bax-proficient cells but not in Bax-deficient cells. These findings suggest that although Bax is not absolutely required for death receptor (DR)-dependent signals, it appears to be a key molecule in TG-regulated mitochondrial events. Bax-deficient cells were relatively more resistant to Apo2L/TRAIL than the Bax-proficient counterparts. However, the combination of Apo2L/TRAIL and TG was more effective in mediating apoptosis in both Bax-proficient and -deficient cells and that was coupled with activation of caspases 8 and 3. Although both agents in combination also induced cytochrome c release into cytosol and caspase 9 activation in Bax-proficient cells, these events were abrogated in Bax-deficient cells. Our results thus suggest that the combination of Apo2L/TRAIL and TG appears to bypass the Bax deficiency-induced defects in the mitochondrial (intrinsic) pathway by engaging the DR5-dependent apoptotic signals (extrinsic pathway).

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References

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koepen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest., 104, 155–162.

  • Boya P, Cohen I, Zamzami N, Vieira HLA and Kroemer G . (2002). Cell Death Differ., 9, 465–467.

  • Burns TF and El-Deiry WS . (2001). J. Biol. Chem., 276, 37879–37886.

  • Deng Y Lin Y and Wu X . (2002). Genes Dev., 16, 33–45.

  • Foyouzi-Youssefi R, Arnaudeau S, Broner C, Kelley WL, Tschopp J, Lew DP, Demaurex N and Krause KH . (2000). Proc. Natl. Acad. Sci. USA, 97, 5723–5728.

  • Furuya Y, Lundmo P, Short AD, Gill DL and Isaacs JT . (1994). Cancer Res., 54, 6167–6175.

  • He Q, Lee DI, Rong R, Yu M, Luo X, Klein M, El-Deiry WS, Huang Y, Hussain A and Sheikh MS . (2002a). Oncogene, 21, 2623–2633.

  • He Q, Luo X, Huang Y and Sheikh MS . (2002b). Oncogene, 21, 6032–6040.

  • Hsu YT, Wolter KG and Youle RJ . (1997). Proc. Natl. Acad. Sci. USA, 94, 3668–3672.

  • Huang Y, He Q, Rong R, Hillman MJ and Sheikh MS . (2001). Cancer Res., 61, 6918–6924.

  • Jin Z, Dicker DT and El-Deiry WS . (2002). Cell Cycle, 1, 82–89.

  • Johnstone RW, Ruefli AA and Lowe SW . (2002) Cell, 108, 153–164.

  • Kim BC, Kim HT, Mamura M, Ambudkar IS, Choi KS and Kim SJ . (2002). J. Biol. Chem., 277, 31381–31389.

  • Krebs J . (1998). BioMetals, 11, 375–382.

  • LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, schow P, Fong S, Schwall R, Sinicropi D and Askenazi A . (2002). Nat. Med., 8, 274–281.

  • Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E and Saikumar P . (2003). J. Biol. Chem., 278, 5367–5376.

  • Murphy AN, Bredesen E, Cortopassi G, Wang E and Fiskum G . (1996). Proc. Natl. Acad. Sci. USA, 93, 9893–9898.

  • Nechushtan A, Smith CL, Hsu YT and Youle RJ . (1999). EMBO J., 18, 2330–2341.

  • Nicholson DW . (2000). Nature, 407, 810–816.

  • Nutt LK, Chandra J, Pataer A, Fang B, Roth JA, Swisher SG, O'Neil RG and McConkey DJ . (2002a). J. Biol. Chem., 277, 20301–20308.

  • Nutt LK, Pataer A, Pahler J, Fang B, Roth JA, McConkey DJ and Swisher SG . (2002b). J. Biol. Chem., 277, 9219–9225.

  • Reed JC . (2002). Nat. Rev. Drug Dev., 1, 111–121.

  • Sagara Y and Inesi G . (1991). J. Biol. Chem., 266, 13503–13506.

  • Shimizu S, Eguchi Y, Kamiike W, Funahashi Y, Mignon A, Lacronique V, Matsuda H and Tsujimoto Y . (1998). Proc. Natl. Acad. Sci. USA, 95, 1455–1459.

  • Shimizu S, Narita M and Tsujimoto Y . (1999). Nature, 399, 483–487.

  • Tombal B, Denmeade SR, Gillis JM and Isaacs JT . (2002). Cell Death Differ., 9, 561–573.

  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163

  • Wang X . (2001). Gene Dev., 15, 2922–2933.

  • Wertz IE and Dixit VM . (2000). J. Biol. Chem., 275, 11470–11477.

  • Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG and Youle RJ . (1997). J. Cell Biol., 139, 1281–1292.

  • Yang E and Korsmeyer SJ . (1996). Blood, 88, 368–401.

  • Zhang L, Yu J, Park BH, Kinzler KW and Vogelstein B . (2000). Science, 290, 989–992.

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Acknowledgements

We thank Dr Avi Ashkenazi and Genentech for a generous supply of Apo2L/TRAIL and Dr Bert Vogelstein for kindly providing the Bax-proficient and -deficient HCT116 cells. This work was supported in part by United States Army Prostate Cancer Research Program grant DAMD 170010722 and by NIH Grant CA89043.

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  1. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, 13210, NY, USA

    Qin He, JoAnne Montalbano, Chad Corcoran, Weixin Jin, Ying Huang & M Saeed Sheikh

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  1. Qin He
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  2. JoAnne Montalbano
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  4. Weixin Jin
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Correspondence to M Saeed Sheikh.

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He, Q., Montalbano, J., Corcoran, C. et al. Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis. Oncogene 22, 2674–2679 (2003). https://doi.org/10.1038/sj.onc.1206363

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