Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression Journal Article
| Authors: | Wang, Y.; Velho, S.; Vakiani, E.; Peng, S.; Bass, A. J.; Chu, G. C.; Gierut, J.; Bugni, J. M.; Der, C. J.; Philips, M.; Solit, D. B.; Haigis, K. M. |
| Article Title: | Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression |
| Abstract: | N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of infiammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP-ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer. SIGNIFICANCE: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an infiammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. © 2013 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 3 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-03-01 |
| Start Page: | 294 |
| End Page: | 307 |
| Language: | English |
| PROVIDER: | scopus |
| PMCID: | PMC3595397 |
| PUBMED: | 23274911 |
| DOI: | 10.1158/2159-8290.CD-12-0198 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2013" - ":doi 10.1158/2159-8290.CD-12-0198" - "Source: Scopus" |
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