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Tumor-associated protein SPIK/TATI suppresses serine protease dependent cell apoptosis

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Abstract

Serine protease dependent cell apoptosis (SPDCA) is a recently described caspase independent innate apoptotic pathway. It differs from the traditional caspase dependent apoptotic pathway in that serine proteases, not caspases, are critical to the apoptotic process. The mechanism of SPDCA is still unclear and further investigation is needed to determine any role it may play in maintaining cellular homeostasis and development of disease. The current knowledge about this pathway is limited only to the inhibitory effects of some serine protease inhibitors. Synthetic agents such as pefabloc, AEBSF and TPCK can inhibit this apoptotic process in cultured cells. There is little known, however, about biologically active agents available in the cell which can inhibit SPDCA. Here, we show that over-expression of a cellular protein called serine protease inhibitor Kazal (SPIK/TATI/PSTI) results in a significant decrease in cell susceptibility to SPDCA, suggesting that SPIK is an apoptosis inhibitor suppressing this pathway of apoptosis. Previous work has associated SPIK and cancer development, indicating that this finding will help to open the doorway for further study on the mechanism of SPDCA and the role it may play in cancer development.

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Abbreviations

BFA:

Brefeldin A

CDCA:

Caspase dependent cell apoptosis

CHX:

cycloheximide

SPDCA:

Serine protease dependent cell apoptosis

SPIK:

Serine protease inhibitor Kazal

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22:299–306

    Article  PubMed  CAS  Google Scholar 

  3. Nunez G, Benedict MA, Hu Y, Inohara N (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237–3245

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM et al (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. Embo J 17:2215–2223

    Article  PubMed  CAS  Google Scholar 

  6. Egger L, Schneider J, Rheme C, Tapernoux M, Hacki J, Borner C (2003) Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ 10:1188–1203

    Article  PubMed  CAS  Google Scholar 

  7. Thorburn J, Bender LM, Morgan MJ, Thorburn A (2003) Caspase- and serine protease-dependent apoptosis by the death domain of FADD in normal epithelial cells. Mol Biol Cell 14:67–77

    Article  PubMed  CAS  Google Scholar 

  8. Abate A, Schroder H (1998) Protease inhibitors protect macrophages from lipopolysaccharide-induced cytotoxicity: possible role for NF-[kappa]B. Life Sci 62:1081–1088

    Article  PubMed  CAS  Google Scholar 

  9. Graf R, Bimmler D (2006) Biochemistry and biology of SPINK-PSTI and monitor peptide. Endocr Metab Clin North Am 35:333–43, ix

    Google Scholar 

  10. Stenman UH (2002) Tumor-associated trypsin inhibitor. Clin Chem 48:1206–1209

    PubMed  CAS  Google Scholar 

  11. Paju A, Stenman UH (2006) Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 43:103–142

    Article  PubMed  CAS  Google Scholar 

  12. Greene LJ, Pubols MH, Bartelt DC (1976) Human pancreatic secretory trypsin inhibitor. Methods Enzymol 45:813–25

    Article  PubMed  CAS  Google Scholar 

  13. Ohmachi Y, Murata A, Matsuura N, Yasuda T, Uda K, Mori T (1994) Overexpression of pancreatic secretory trypsin inhibitor in pancreatic cancer. Evaluation of its biological function as a growth factor. Int J Pancreatol 15:65–73

    PubMed  CAS  Google Scholar 

  14. Tomita N, Doi S, Higashiyama M, Morimoto H, Murotani M, Kawasaki Y et al (1990) Expression of pancreatic secretory trypsin inhibitor gene in human colorectal tumor. Cancer 66:2144–2149

    Article  PubMed  CAS  Google Scholar 

  15. Lukkonen A, Lintula S, von Boguslawski K, Carpen O, Ljungberg B, Landberg G et al (1999) Tumor-associated trypsin inhibitor in normal and malignant renal tissue and in serum of renal-cell carcinoma patients. Int J Cancer 83:486–490

    Article  PubMed  CAS  Google Scholar 

  16. Tonouchi A, Ohtsuka M, Ito H, Kimura F, Shimizu H, Kato M et al (2006) Relationship between pancreatic secretory trypsin inhibitor and early recurrence of intrahepatic cholangiocarcinoma following surgical resection. Am J Gastroenterol 101:1601–1610

    Article  PubMed  CAS  Google Scholar 

  17. Lee YC, Pan HW, Peng SY, Lai PL, Kuo WS, Ou YH et al (2007) Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma. Eur J Cancer 43:736–744

    Article  PubMed  CAS  Google Scholar 

  18. Anderson KM, Alrefai W, Bonomi P, Seed TM, Dudeja P, Hu Y et al (2003) Caspase-dependent and -independent Panc-1 cell death due to actinomycin D and MK 886 are additive but increase clonogenic survival. Exp Biol Med 228:915–925

    CAS  Google Scholar 

  19. Tian M, Kamoun S (2005) A two disulfide bridge Kazal domain from Phytophthora exhibits stable inhibitory activity against serine proteases of the subtilisin family. BMC Biochem 6:15

    Article  PubMed  CAS  Google Scholar 

  20. Moffitt KL, Martin SL, Walker B (2007) The emerging role of serine proteases in apoptosis. Biochem Soc Trans 35:559–560

    Article  PubMed  CAS  Google Scholar 

  21. Yasuda T, Ogawa M, Murata A, Ohmachi Y, Yasuda T, Mori T et al (1993) Identification of the IL-6-responsive element in an acute-phase-responsive human pancreatic secretory trypsin inhibitor-encoding gene. Gene 131:275–280

    Article  PubMed  CAS  Google Scholar 

  22. Uda K-I, Murata A, Nishijima J-I, Doi S, Tomita N, Ogawa M et al (1994) Elevation of circulating monitor peptide/pancreatic secretory trypsin inhibitor-I (PSTI-61) after turpentine-induced inflammation in rats: hepatocytes produce it as an acute phase reactant. J Surg Res 57:563–568

    Article  PubMed  CAS  Google Scholar 

  23. Ohmachi Y, Murata A, Yasuda T, Kitagawa K, Yamamoto S, Monden M et al (1994) Expression of the pancreatic secretory trypsin inhibitor gene in the liver infected with hepatitis B virus. J Hepatol 21:1012–1016

    Article  PubMed  CAS  Google Scholar 

  24. Lu X, Block T (2004) Study of the early steps of the hepatitis B virus life cycle. Int J Med Sci 1:21–33

    PubMed  Google Scholar 

  25. Chisari FV, Ferrari C (1995) Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13:29–60

    Article  PubMed  CAS  Google Scholar 

  26. Rocken C, Carl-McGrath S (2001) Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis 19:269–278

    Article  PubMed  CAS  Google Scholar 

  27. Guidotti LG, Chisari FV (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23–61

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported by an Appropriation from the Commonwealth of Pennsylvania and National Cancer Institute, NIH. We thank Drs. C. Satishchandra and Tian-lun Zhou (Nucleonics Inc., Horsham, PA) for their helpful advice and for providing the Huh7T cell line. We also thank Drs. Andy Cuconati and Kunwar Shailubhai (Institute for Hepatitis and Virus Research, Doylestown, PA) for their critical reading.

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Authors and Affiliations

  1. Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, College of Medicine, Drexel University, 3805 Old Easton Road, Doylestown, PA, 18902, USA

    Xuanyong Lu, Felix Lu & Timothy M. Block

  2. Institute for Hepatitis and Virus Research, Doylestown, PA, 18902, USA

    Jason Lamontagne & Timothy M. Block

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  1. Xuanyong Lu
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  2. Jason Lamontagne
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  3. Felix Lu
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Correspondence to Xuanyong Lu.

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Lu, X., Lamontagne, J., Lu, F. et al. Tumor-associated protein SPIK/TATI suppresses serine protease dependent cell apoptosis. Apoptosis 13, 483–494 (2008). https://doi.org/10.1007/s10495-008-0193-x

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