Advertisement

Cancer-Selective Apoptosis by Tumor Suppressor Par-4

  • Nikhil Hebbar
  • Tripti Shrestha-Bhattarai
  • Vivek M. RangnekarEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 818)

Abstract

Tumor suppressor genes play an important role in preventing neoplastic transformation and maintaining normal tissue homeostasis. Par-4 is one such tumor suppressor which is unique in its ability to selectively induce apoptosis in cancer cells while leaving the normal cells unaffected. The cancer cell specific activity of Par-4 is elicited through intracellular as well as extracellular mechanisms. Intracellularly Par-4 acts through the inhibition of pro-survival pathways and activation of Fas mediated apoptosis whereas extracellular (secreted Par-4) acts by binding to cell surface GRP78 leading to activation of the extrinsic apoptotic pathway. Many studies have highlighted the importance of Par-4 not only in preventing cancer development/recurrence but also as a promising anticancer therapeutic agent.

Keywords

Par-4/PAWR Apoptosis Tumor suppressor protein Extracellular systemic effects Prostate cancer 

Notes

Acknowledgments

This study was supported by KLCR grant and NIH/NCI grant CA060872 (to VMR). The authors thank the past and present members of the Rangnekar Laboratory and collaborators who contributed to the work described in this review article.

References

  1. 1.
  2. 2.
    Salama JK, Vokes EE (2013) New radiotherapy and chemoradiotherapy approaches for non-small-cell lung cancer. J Clin Oncol 31(8):1029–1038PubMedCrossRefGoogle Scholar
  3. 3.
    Lim KH et al (2012) Neoadjuvant therapy of pancreatic cancer: the emerging paradigm? Oncologist 17(2):192–200PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Bjorkholm M et al (2011) Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol 29(18):2514–2520PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Alvarez RH, Valero V, Hortobagyi GN (2010) Emerging targeted therapies for breast cancer. J Clin Oncol 28(20):3366–3379PubMedCrossRefGoogle Scholar
  6. 6.
    Sells SF et al (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ 5(4):457–466PubMedGoogle Scholar
  7. 7.
    Johnstone RW et al (1998) Mapping of the human PAWR (par-4) gene to chromosome 12q21. Genomics 53(2):241–243PubMedCrossRefGoogle Scholar
  8. 8.
    Cook J et al (1999) Decreased expression of the pro-apoptotic protein Par-4 in renal cell carcinoma. Oncogene 18(5):1205–1208PubMedCrossRefGoogle Scholar
  9. 9.
    Boehrer S et al (2001) Deregulated expression of prostate apoptosis response gene-4 in less differentiated lymphocytes and inverse expressional patterns of par-4 and bcl-2 in acute lymphocytic leukemia. Hematol J 2(2):103–107PubMedCrossRefGoogle Scholar
  10. 10.
    Alvarez JV et al (2013) Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 24(1):30–44PubMedCrossRefGoogle Scholar
  11. 11.
    Vetterkind S et al (2005) Ectopic expression of Par-4 leads to induction of apoptosis in CNS tumor cell lines. Int J Oncol 26(1):159–167PubMedGoogle Scholar
  12. 12.
    Moreno-Bueno G et al (2007) Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. Cancer Res 67(5):1927–1934PubMedCrossRefGoogle Scholar
  13. 13.
    Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9(7):517–531PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Pruitt K et al (2005) Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. J Biol Chem 280(24):23363–23370PubMedCrossRefGoogle Scholar
  15. 15.
    Diaz-Meco MT, Abu-Baker S (2009) The Par-4/PTEN connection in tumor suppression. Cell Cycle 8(16):2518–2522PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Goswami A et al (2005) Binding and phosphorylation of par-4 by akt is essential for cancer cell survival. Mol Cell 20(1):33–44PubMedCrossRefGoogle Scholar
  17. 17.
    Goswami A, Ranganathan P, Rangnekar VM (2006) The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Res 66(6):2889–2892PubMedCrossRefGoogle Scholar
  18. 18.
    Ishizawar R, Parsons SJ (2004) c-Src and cooperating partners in human cancer. Cancer Cell 6(3):209–214PubMedCrossRefGoogle Scholar
  19. 19.
    Kline CL, Irby RB (2011) The pro-apoptotic protein Prostate Apoptosis Response Protein-4 (Par-4) can be activated in colon cancer cells by treatment with Src inhibitor and 5-FU. Apoptosis 16(12):1285–1294PubMedCrossRefGoogle Scholar
  20. 20.
    Hebbar N, Wang C, Rangnekar VM (2012) Mechanisms of apoptosis by the tumor suppressor Par-4. J Cell Physiol 227(12):3715–3721PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    El-Guendy N et al (2003) Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells. Mol Cell Biol 23(16):5516–5525PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    El-Guendy N, Rangnekar VM (2003) Apoptosis by Par-4 in cancer and neurodegenerative diseases. Exp Cell Res 283(1):51–66PubMedCrossRefGoogle Scholar
  23. 23.
    Chakraborty M et al (2001) Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. Cancer Res 61(19):7255–7263PubMedGoogle Scholar
  24. 24.
    Nalca A et al (1999) Oncogenic Ras sensitizes cells to apoptosis by Par-4. J Biol Chem 274(42):29976–29983PubMedCrossRefGoogle Scholar
  25. 25.
    Wajant H (2002) The Fas signaling pathway: more than a paradigm. Science 296(5573):1635–1636PubMedCrossRefGoogle Scholar
  26. 26.
    Gurumurthy S et al (2005) Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Mol Cell Biol 25(3):1146–1161PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Johnstone RW et al (1996) A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms’ tumor suppressor WT1. Mol Cell Biol 16(12):6945–6956PubMedCentralPubMedGoogle Scholar
  28. 28.
    Qiu G et al (1999) Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. Oncogene 18(3):623–631PubMedCrossRefGoogle Scholar
  29. 29.
    Cheema SK et al (2003) Par-4 transcriptionally regulates Bcl-2 through a WT1-binding site on the bcl-2 promoter. J Biol Chem 278(22):19995–20005PubMedCrossRefGoogle Scholar
  30. 30.
    Diaz-Meco MT et al (1996) The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86(5):777–786PubMedCrossRefGoogle Scholar
  31. 31.
    Roussigne M et al (2003) THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Oncogene 22(16):2432–2442PubMedCrossRefGoogle Scholar
  32. 32.
    Kawai T, Akira S, Reed JC (2003) ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Mol Cell Biol 23(17):6174–6186PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Page G et al (1999) Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. Oncogene 18(51):7265–7273PubMedCrossRefGoogle Scholar
  34. 34.
    Goswami A et al (2008) Par-4 binds to topoisomerase 1 and attenuates its DNA relaxation activity. Cancer Res 68(15):6190–6198PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Zhao Y et al (2007) Cancer resistance in transgenic mice expressing the SAC module of Par-4. Cancer Res 67(19):9276–9285PubMedCrossRefGoogle Scholar
  36. 36.
    Burikhanov R et al (2009) The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138(2):377–388PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Zhao Y et al (2011) Systemic Par-4 inhibits non-autochthonous tumor growth. Cancer Biol Ther 12(2):152–157PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Nikhil Hebbar
    • 1
  • Tripti Shrestha-Bhattarai
    • 1
  • Vivek M. Rangnekar
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Graduate Center for ToxicologyUniversity of KentuckyLexingtonUSA
  2. 2.Departments of Radiation MedicineUniversity of KentuckyLexingtonUSA
  3. 3.Microbiology, Immunology and Molecular GeneticsUniversity of KentuckyLexingtonUSA
  4. 4.L. P. Markey Cancer CenterUniversity of KentuckyLexingtonUSA

Personalised recommendations