Tumour maintenance is mediated by eNOS

Abstract

Endothelial nitric oxide synthase (eNOS) is shown to have a role in cellular transformation and tumour maintenance downstream of Ras–AKT signalling. eNOS exerts its effect through nitrosylation and activation of endogenous wild-type Ras proteins. Tumour cells become addicted to the expression of initiating oncogenes like Ras, such that loss of oncogene expression in established tumours leads to tumour regression1. HRas, NRas or KRas are mutated to remain in the active GTP-bound oncogenic state in many cancers2. Although Ras activates several proteins to initiate human tumour growth, only PI3K, through activation of protein kinase B (PKB; also known as AKT), must remain activated by oncogenic Ras to maintain this growth3. Here we show that blocking phosphorylation of the AKT substrate, endothelial nitric oxide synthase (eNOS or NOS3), inhibits tumour initiation and maintenance. Moreover, eNOS enhances the nitrosylation and activation of endogenous wild-type Ras proteins, which are required throughout tumorigenesis. We suggest that activation of the PI3K–AKT–eNOS–(wild-type) Ras pathway by oncogenic Ras in cancer cells is required to initiate and maintain tumour growth.