The role of K-Ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines

Abstract

Purpose Pancreatic ductal and lung adenocarcinomas are the most common and prevalent types of human neoplasms with a greater than 80% mortality rate. The poor prognosis of both these cancers are likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. Most notably, the early development of pancreatic intraepithelial neoplasia and lung lesions is suggested to be the result of a mutation in the K-ras (G12D) oncogene. Tumor necrosis factor-related-apoptosis-inducing-ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells, while leaving normal cells unharmed. However, some cancers show resistance to TRAIL treatment, leaving a gap in the understanding of its exact etiology. Methods TRAIL-induced resistance to cell death was investigated in pancreatic and lung cancer cell lines. Cell survival was determined by SRB and apoptosis by ELISA-based cell death assay. Activation of bid and caspases were evaluated by Western blotting. Results Our study demonstrated that TRAIL significantly suppressed cell survival, by inducing apoptosis in a dose-dependent manner, in the pancreatic cancer BxPC-3 (wild type G12) and lung cancer A549 (G12S) cell lines. In contrast, Panc-1 pancreatic and SK-LU-1 lung cancer cell lines, which have a mutated (G12D) K-ras genotype, were resistant to the actions of TRAIL. Conclusions This study demonstrates an association between TRAIL resistance to apoptosis in human pancreatic and lung cancer cell lines and G12D K-ras12 mutation.

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

“…Our western blots revealed that U0126 directly inhibited the phosphorylation of ERK at 6 and 24 h, followed by inhibiting the activations of its downstream molecules, including cyclinD1 and c-myc but increased the expression of p27 kip1 , BAX, and BIM at 6 and 24 h. MAPK pathway promotes survival by inhibiting the proapoptotic BIM and BAD protein expressions and caspase 9 activity or by activating anti-apoptotic BCL-2 and BCL-XL protein expressions [42,43]. ERK activation also interferes extrinsic apoptotic pathway by inhibiting the death receptors FAS, TRAIL, or TNF [44]. Besides, activated ERK signaling can enhance the expression of CDK inhibitor proteins, p16, p21, and p27, thereby leading to cell cycle arrest at the G1 phase [45,46].…”

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

“…The most frequent among K-RAS mutations is glycine to aspartic acid at codon 12 (G12D), followed by glycine to valine at codon 12. Mutant K-RAS G12D plays a critical role in the development of chemotherapy resistance and cancer progression for several types of cancer, including pancreatic cancer [21,22]. Additionally, recent evidence has shown that K-RAS upregulates bone morphogenetic protein-7 (BMP-7) expression/ secretion.…”

H-Ras regulation of TRAIL death receptor mediated apoptosis

“…Consistent with our data, recent studies have shown that TRAIL-resistant cells were sensitized by combinatorial treatment of TRAIL with cetuximab (an anti-EGFR monoclonal antibody) or sorafenib (a multi-kinase inhibitor that acts on Raf kinases, MEK, and ERK signaling) in different cancer cell lines and tumor xenograft models [39, 40]. By contrast, several other studies suggested an opposite role for oncogenic Ras in TRAIL-induced apoptosis [25-27, 29, 41, 42]. For example, Drosopoulos et al [25] showed that transfection of H-Ras12V or K-Ras12V increased TRAIL-induced apoptosis in a colon cancer cell line caco-2.…”