Evaluating The Role Of Nitric Oxide Synthase In Oncogenic Ras-Driven Tumorigenesis.
We previously reported that oncogenic KRAS activation of the PI3K/AKT pathway stimulates the remaining wild-type HRAS and NRAS proteins in a manner dependent upon both eNOS expression and C118 in HRAS and NRAS, which promoted tumor growth. Interestingly however, we recently found that loss of wild-type HRAS, NRAS, and even more potently, loss of both of these genes actually enhanced oncogenic KRAS-driven early tumorigenesis. Taken together, these results indicate that wild-type RAS proteins are tumor suppressing early in tumorigenesis, but tumor promoting in more malignant settings. Knock-in of a C118S mutation into an endogenous wild-type RAS gene did not, however, hamper oncogenic KRAS-driven tumor initiation. As such, redox-dependent reactions with C118 of wild-type RAS proteins are unlikely to be responsible for the tumor suppressive role of wild-type RAS proteins. This suggests that the redox-dependent reactions with C118 of wild-type RAS proteins are more important in more malignant settings. Given this, it stands to reason that inhibiting redox-dependent reactions like S-nitrosylation of wild-type RAS proteins may be more effective in established cancer settings. Indeed, we find that in three different models of KRAS-driven cancers-skin, pancreatic and lung- the general NOS inhibitor l-NAME reduced tumor burden and/or extended the lifespan of mice. Since oncogenic RAS has so far proven refractory to pharmacologic inhibition, targeting NOS activity may be an actionable approach to inhibiting RAS signaling for the treatment of a broad spectrum of cancers.
Duke University Medical Center, Durham, USA.
Chris
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D019943:Amino Acid Substitution; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins