Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation

Mansoor M. Ahmed, David Sheldon, Mushtaq A. Fruitwala, Kolaparthi Venkatasubbarao, Eun Y. Lee, Seema Gupta, Craig Wood, Mohammed Mohiuddin, William E. Strodel

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Oncogenic ras is known to inhibit cell death and growth inhibitory genes and activate prosurvival genes. Proapoptotic gene PAR-4, has been found to be downregulated by oncogenic ras. Since pancreatic tumors harbor a high incidence of K-ras point mutations, we hypothesized that oncogenic K-ras might influence the function and expression of PAR-4. PAR-4 expression levels were analyzed in 4 established pancreatic tumor cell lines, 10 normal pancreatic tissues, 44 frozen tumor tissues and 25 paraffin-embedded pancreatic adenocarcinoma samples by Real Time RT-PCR, Western blot analysis and immunohistochemistry. K-ras mutational status was analyzed by allele-specific oligonucleotide-hybridization. Expression levels of PAR-4 were correlated with the K-ras mutational status and clinical characteristics. Further, modulation of endogenous PAR-4 was tested by transiently expressing oncogenic ras in a wild-type K-ras pancreatic cancer cell line, BxPC-3. Three cell lines with K-ras mutations showed low levels of PAR-4 when compared to a normal pancreatic tissue. Of 44 frozen tumors, 16 showed appreciable upregulation of Par mRNA and 27 showed significant downregulation of PAR-4 mRNA when compared to normal pancreatic tissue and 1 had levels equivalent to normal pancreatic tissue. Of 25 paraffin-embedded tumors, 9 showed downregulation of PAR-4 protein and this downregulation of PAR-4 correlated significantly with K-ras mutational status (p < 0.00002). In addition, the presence of PAR-4 mRNA or protein expression in pancreatic tumors correlated with prolonged survival. Transient overexpression of oncogenic ras in wild-type K-ras BxPC-3 cells significantly downregulated the endogenous PAR-4 protein levels and conferred accelerated growth. Thus, downregulation or loss of PAR-4 expression by oncogenic ras may provide a selective survival advantage for pancreatic tumors, through inhibition of proapoptotic pathway mediated bv PAR-4.

Original languageEnglish (US)
Pages (from-to)63-70
Number of pages8
JournalInternational Journal of Cancer
Volume122
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • K-ras mutation
  • PAR-4
  • Pancreatic cancer
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ahmed, M. M., Sheldon, D., Fruitwala, M. A., Venkatasubbarao, K., Lee, E. Y., Gupta, S., Wood, C., Mohiuddin, M., & Strodel, W. E. (2008). Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation. International Journal of Cancer, 122(1), 63-70. https://doi.org/10.1002/ijc.23019