Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.

TitleMutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.
Publication TypeJournal Article
Year of Publication2013
AuthorsWang, Y, Velho, S, Vakiani, E, Peng, S, Bass, AJ, Chu, GC, Gierut, J, Bugni, JM, Der, CJ, Philips, M, Solit, DB, Haigis, KM
JournalCancer Discov
Volume3
Issue3
Pagination294-307
Date Published2013 Mar
ISSN2159-8290
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 inflammation. 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.

DOI10.1158/2159-8290.CD-12-0198
Alternate JournalCancer Discov
PubMed ID23274911
PubMed Central IDPMC3595397
Grant ListCA118425 / CA / NCI NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States
K01 CA118425 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 CA163489 / CA / NCI NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States