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TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4

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Abstract

Although it is conventionally regarded as an inflammatory caspase, recent studies have shown that caspase-4 plays a role in induction of apoptosis by endoplasmic reticulum (ER) stress. We report here that activation of caspase-4 is also involved in induction of apoptosis by TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. Treatment with TRAIL resulted in activation of caspase-4. This appeared to be mediated by caspase-3, in that caspase-4 was activated later than caspase-8, -9, and -3, and that inhibition of caspase-3 blocked TRAIL-induced caspase-4 activation. Notably, TRAIL triggered ER stress in melanoma cells as shown by up-regulation of the GRP78 protein and the spliced form of XBP-1 mRNA. This seemed to be necessary for activation of caspase-4, as activation of caspase-3 by agents that did not trigger ER stress did not cause activation of caspase-4. Importantly, inhibition of caspase-4 also partially blocked caspase-3 activation, suggesting that activation of caspase-4 may be positive feed-back mechanism to further enhance caspase-3 activation. Collectively, these results show that activation of caspase-4 contributes to TRAIL-induced apoptosis and is associated with induction of ER stress by TRAIL in melanoma cells, and may have important implications for improving therapeutic efficacies of TRAIL in melanoma.

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References

  1. Griffith TS, Lynch DH (1998) TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 10:559–563

    Article  CAS  PubMed  Google Scholar 

  2. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113

    Article  CAS  PubMed  Google Scholar 

  3. Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, Holler N, Tschopp J (1997) TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7:831–836

    Article  CAS  PubMed  Google Scholar 

  4. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A (2000) Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12:611–620

    Article  CAS  PubMed  Google Scholar 

  5. Yamada H, Tada-Oikawa S, Uchida A, Kawanishi S (1999) TRAIL causes cleavage of bid by caspase-8 and loss of mitochondrial membrane potential resulting in apoptosis in BJAB cells. Biochem Biophys Res Commun 265:130–133

    Article  CAS  PubMed  Google Scholar 

  6. Han J, Goldstein LA, Gastman BR, Rabinowich H (2006) Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. J Biol Chem 281:10153–10163

    Article  CAS  PubMed  Google Scholar 

  7. Gillespie S, Borrow J, Zhang XD, Hersey P (2006) Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 11:2251–2265

    Article  CAS  PubMed  Google Scholar 

  8. Wagner KW, Engels IH, Deveraux QL (2004) Caspase-2 can function upstream of bid cleavage in the TRAIL apoptosis pathway. J Biol Chem 279:35047–35052

    Article  CAS  PubMed  Google Scholar 

  9. Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K (2005) Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J 24:3532–3542

    Article  CAS  PubMed  Google Scholar 

  10. Martinon F, Tschopp J (2007) Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14:10–22

    Article  CAS  PubMed  Google Scholar 

  11. Kamada S, Funahashi Y, Tsujimoto Y (1997) Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ 4:473–478

    Article  PubMed  Google Scholar 

  12. Kamada S, Washida M, Hasegawa J, Kusano H, Funahashi Y, Tsujimoto Y (1997) Involvement of caspase-4(-like) protease in Fas-mediated apoptotic pathway. Oncogene 15:285–290

    Article  CAS  PubMed  Google Scholar 

  13. Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and a beta-induced cell death. J Cell Biol 165:347–356

    Article  CAS  PubMed  Google Scholar 

  14. Fischer H, Koenig U, Eckhart L, Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293:722–726

    Article  CAS  PubMed  Google Scholar 

  15. Boyce M, Yuan J (2006) Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ 13:363–373

    Article  CAS  PubMed  Google Scholar 

  16. Jiang CC, Chen LH, Gillespie S, Wang YF, Kiejda KA, Zhang XD, Hersey P (2007) Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res 67:9750–9761

    Article  CAS  PubMed  Google Scholar 

  17. Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3:E255–E263

    Article  CAS  PubMed  Google Scholar 

  18. Obeng EA, Boise LH (2005) Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. J Biol Chem 280:29578–29587

    Article  CAS  PubMed  Google Scholar 

  19. Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Droin N, Ulevitch RJ, Green DR, Nicholson DW (2006) Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440:1064–1068

    Article  CAS  PubMed  Google Scholar 

  20. Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499

    Article  CAS  PubMed  Google Scholar 

  21. Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6:45–54

    Article  CAS  PubMed  Google Scholar 

  22. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103

    Article  CAS  PubMed  Google Scholar 

  23. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276:35–40

    Google Scholar 

  24. Hersey P, Zhang XD (2001) How melanoma cells evade trail-induced apoptosis. Nat Rev Cancer 1:142–150

    Article  CAS  PubMed  Google Scholar 

  25. Zhang XD, Zhang XY, Gray CP, Nguyen T, Hersey P (2001) Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Cancer Res 61:7339–7348

    CAS  PubMed  Google Scholar 

  26. Chen LH, Jiang CC, Watts R, Thorne RF, Kiejda KA, Zhang XD, Hersey P (2008) Inhibition of endoplasmic reticulum stress-induced apoptosis of melanoma cells by the ARC protein. Cancer Res 68:834–842

    Article  CAS  PubMed  Google Scholar 

  27. Nakamura M, Gotoh T, Okuno Y, Tatetsu H, Sonoki T, Uneda S, Mori M, Mitsuya H, Hata H (2006) Activation of the endoplasmic reticulum stress pathway is associated with survival of myeloma cells. Leuk Lymphoma 47:531–539

    Article  CAS  PubMed  Google Scholar 

  28. Wang YF, Jiang CC, Kiejda KA, Gillespie S, Zhang XD, Hersey P (2007) Apoptosis induction in human melanoma cells by inhibition of MEK is caspase-independent and mediated by the Bcl-2 family members PUMA, Bim, and Mcl-1. Clin Cancer Res 13:4934–4942

    Article  CAS  PubMed  Google Scholar 

  29. Fu Y, Li J, Lee AS (2007) GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res 67:3734–3740

    Article  CAS  PubMed  Google Scholar 

  30. Zhang XD, Gillespie SK, Hersey P (2004) Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways. Mol Cancer Ther 3:187–197

    CAS  PubMed  Google Scholar 

  31. Hirota M, Kitagaki M, Itagaki H, Aiba S (2006) Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. J Toxicol Sci 31:149–156

    Article  CAS  PubMed  Google Scholar 

  32. Lee AS (2005) The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35:373–381

    Article  CAS  PubMed  Google Scholar 

  33. Zhang XD, Wu JJ, Gillespie S, Borrow J, Hersey P (2006) Human melanoma cells selected for resistance to apoptosis by prolonged exposure to tumor necrosis factor-related apoptosis-inducing ligand are more vulnerable to necrotic cell death induced by cisplatin. Clin Cancer Res 12:1355–1364

    Article  CAS  PubMed  Google Scholar 

  34. Zhu BK, Wang P, Zhang XD, Jiang CC, Chen LH, Avery-Kiejda KA, Watts R, Hersey P (2008) Activation of Jun N-terminal kinase is a mediator of vincristine-induced apoptosis of melanoma cells. Anticancer Drugs 19:189–200

    Article  CAS  PubMed  Google Scholar 

  35. Yang X, Wang J, Liu C, Grizzle WE, Yu S, Zhang S, Barnes S, Koopman WJ, Mountz JD, Kimberly RP, Zhang HG (2005) Cleavage of p53-vimentin complex enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of rheumatoid arthritis synovial fibroblasts. Am J Pathol 167:705–719

    CAS  PubMed  Google Scholar 

  36. Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM (2009) The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138:377–388

    Article  CAS  PubMed  Google Scholar 

  37. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144:281–292

    Article  CAS  PubMed  Google Scholar 

  38. Chen LH, Jiang CC, Kiejda KA, Wang YF, Thorne RF, Zhang XD, Hersey P (2007) Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response. Carcinogenesis 28:2328–2336

    Article  CAS  PubMed  Google Scholar 

  39. Jiang CC, Chen LH, Gillespie S, Kiejda KA, Mhaidat N, Wang YF, Thorne R, Zhang XD, Hersey P (2007) Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response. Cancer Res 67:5880–5888

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the NSW State Cancer Council, the Melanoma and Skin Cancer Research Institute Sydney, the Hunter Melanoma Foundation, NSW, and the National Health and Medical Research Council, Australia. X. D. Zhang is a Cancer Institute NSW Fellow.

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Correspondence to Peter Hersey or Xu Dong Zhang.

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Mao, Z.G., Jiang, C.C., Yang, F. et al. TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4. Apoptosis 15, 1211–1222 (2010). https://doi.org/10.1007/s10495-010-0513-9

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