Role of Cell Death Regulatory Genes and Radiation Response in Pancreatic Adenocarcinomas

Abstract

Gene expression studies have revealed that there is more than one cellular pathway governing growth inhibition and apoptosis. Mutations in the ras oncogene that(activate ras) are known to lead to the inactivation of genes that are directly involved in these pathways of growth inhibition and apoptosis. Oncogenic activated ras inhibits TGF-P signalling through the down-regulation of RII expression and abrogates apoptotic pathways through down-modulation of PAR-4 gene expression. A majority of pancreatic turnours harbour K-ras point mutations and these mutations dysregulate, the growth inhibition and apoptosis processes. This leads us to hypothesize that K-ras mutant phenotype status in pancreatic turnours will alter the expression of the RII and PAR-4 genes, and would further dysregulate growth inhibitory and apoptotic processes. In this study, the majority of pancreatic turnours showed down-regulation of RII and PAR-4 gene expression. A strong correlation of down-regulation of RII and PAR-4 with K-ras mutational status was observed. In particular, down regulation of PAR-4 correlated with poor survival in patients with pancreatic adenocarcinomas. Blocking the function of oncogenic ras by using a famesyltransferase inhibitor (Frl) restored RII expression and TGF-P signalling, and this caused enhanced sensitivity of cell lines to radiation. The restoration of RH function by FrI was linked to down-modulation of DNA methyltransferase enzyme that is often implicated in hypermethylation of promoters. Over-expression of RII in pancreatic tumour cells led to the restoration of TGF-P signalling and enhancement of radiation sensitivity. Induction of the pro-apoptotic effector gene, bav (bcI-2 family member) by radiation in RII over-expressed pancreatic cancer cells, was found to be a key mechanism involved in radiation sensitivity. Overexpression of PAR-4 sensitized the cells to radiation and this sensitization was linked to down-modulation of radiation induced Bcl-2 protein. Together, these findings strongly suggest that the restoration of function of the key growth inhibitory and cell death genes RII and PAR-4, which are affected by oncogenic ras mutations in pancreatic turnours will restore and enhance cellular responses to radiation induced clonogenic inhibition and apoptosis