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| Tumorigenesis: eNOS is enough
Oncogenic KRas initiates and maintains tumor growth by stimulating the PI3K–AKT–eNOS signaling pathway, which activates wild-type HRas and NRas. Human cancers frequently contain mutations in Ras GTPase family members. The phosphoinositide 3-kinase (PI3K)–AKT effector pathway is necessary to maintain Ras-mediated tumorigenesis, but the signaling events downstream of PI3K and AKT that are critical for tumor maintenance remain to be defined. In Nature, Kian-Huat Lim, Brooke B. Ancrile, David F. Kashatus and Christopher M. Counter now report that AKT-mediated activation of endothelial nitric oxide synthase (eNOS) maintains tumor growth resulting from oncogenic KRas by promoting the activation of other Ras family members.
Counter and colleagues examined the contribution of various PI3K effectors in tumor maintenance, and found that small hairpin RNA-mediated inhibition of the known AKT substrate eNOS blocked tumorigenesis in PI3K-transformed cells. AKT phosphorylates eNOS on serine 1117, and expression of the non-phosphorylatable mutant eNOSS1117A did not rescue eNOS deficiency. Therefore, eNOS is an important effector of PI3K-mediated tumorigenesis. eNOS catalyzes nitric oxide synthesis, which promotes Ras nitrosylation and GTP binding. Constitutive PI3K signaling stimulated nitrosylation and GTP loading of endogenous NRas and HRas in KRas-deficient cells. Ras activation was blocked by pharmacologic inhibition of PI3K or depletion of eNOS. In vivo, eNOS depletion inhibited the tumorigenesis of HRas-transformed cells, which was rescued by eNOS, but not eNOSS1117A. Furthermore, a chemical carcinogen that specifically elicits oncogenic HRas mutations caused significantly fewer tumors in eNOS-/- mice than their wild-type counterparts. Whereas eNOS clearly affects H- and NRas activity, KRas mutations prevail in human cancers. Over 90% of human pancreatic carcinomas contain mutationally activated KRas, and active eNOS was detected in both human pancreatic cancer cell lines and tumor samples. Depletion of eNOS significantly reduced the size and growth rate of tumor cells in vitro and blocked growth of established tumors in vivo. eNOS stimulates Ras activity by facilitating GTP loading; therefore, eNOS should not affect mutationally activated and constitutively GTP-bound KRas. Why, then, does loss of eNOS block KRas-mediated tumor growth? Interestingly, depletion of endogenous, wild-type HRas and NRas in pancreatic cancer cells restricted tumor growth. Re-introduction of HRas or NRas, but not nitrosylation-deficient HRas or NRas, rescued growth, suggesting that eNOS-mediated nitrosylation and activation of endogenous HRas and NRas is critical for the growth and maintenance of KRas-mutant tumors. These data describe the existence of a positive-feedback circuit whereby oncogenic KRas activates PI3K and AKT to promote eNOS phosphorylation, which in turn stimulates formation of active HRas and NRas to maintain tumor growth. Pharmacologic inhibition of eNOS was previously shown to block tumor progression, and this study suggests a biological mechanism for this effect. Whether this pathway is maintained in tumors derived from mutant NRas, HRas or other Ras family members will be interesting to determine. Emily J. Chenette Reference | |
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