RAS Mutations Affect Tumor Necrosis Factor–Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects

Abstract

More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-A (TNFA)-induced apoptosis. When the dynamics of phosphorylated ERK response to TNFA were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-A. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-A autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFA treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. [Cancer Res 2009;69(20):8191-9]

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

“…AKT and ERK activation were indeed observed in K-ras mutated DLD1 cells. [25][26][27] Our data showed that Bcl-2 expression in DLD1 cells was nearly diminished by AKT or ERK inhibitor (Supplementary Figure 7b). Therefore, Bcl-2 expression in DLD1 cells may be through the activation of ERK and AKT signaling pathway.…”

Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation

“…In rat pulmonary myofibroblasts, VP induced ERK-1/2 activation and that the activation was oxidant dependent and EGFR-mediated [36]. In colon, cancer cells lines, it has been demonstrated that KRAS mutational status impacts the apoptotic response mediated by TNF-␣ and extracellular signal-related kinases (ERK) pathway activation [37]. Thus, the finding that Kras tumor mutation is correlated with increased MAPK pathway activation could be consistent with either an oxidative stress/Kras-mediated mechanism or an inflammatory microenvironment/Kras-mediated mechanism [23].…”

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas Q61L )-driven SerpinB2 expression

“…Studies suggest that MKP-mediated negative feedback is a major determinant of pathway activity in Ras/ERK-driven cancers (8). Increased MKP levels are detected in a variety of cancer cells with activated KRas or BRaf and are presumed to suppress ERK activity (9)(10)(11)(12). Ectopic expression of DUSP5 in lung and colon cancer cells lowers ERK activity and suppresses growth (13).…”