Src takes center stage in chronic stress -induced tumor growth

Clinical studies demonstrate that chronic stress, depression, and other behavioral factors influence cancer progression. However, the underlying mechanisms are not fully understood. Src, a non-receptor tyrosine kinase, is a central converging point for many cancer signaling pathways. In this study, we examined the biological and clinical significance of Src in stress mediated tumor growth. Norepinephrine (NE) rapidly activated SrcY419 in β-adrenergic receptor (ADRB) positive ovarian (HeyA8, SKOV3ip1), breast (MBA-231), melanoma (C8161) and prostate (PC-3) cancer cell lines, but not in ADRB-null ovarian cancer cells (A2780-PAR) Confocal microscopy showed that Src was rapidly recruited to the cellular membrane after NE exposure in ADRB positive ovarian cancer cells. Furthermore, treatment with different ADRB agonists and blockers determined that ADRB1/2 are required for SrcY419 phosphorylation. Treatment with a cAMP agonist or PKA agonist/antagonists demonstrated that cAMP/PKA signaling is required for NE-induced Src activation. The unexpected tyrosine phosphorylation via cAMP/PKA activation was found to be mediated by direct phosphorylation of SrcS17 following NE treatment. In Src -/- cells transiently expressing Src, NE caused SrcY419 phosphorylation, which was absent in the Src S17A (mutated) cells. Exposure to NE resulted in an increase in ovarian cancer cell migration and invasion that was completely abrogated by Src-targeted siRNA (P < 0.01). In an orthotopic mouse model of ovarian carcinoma (HeyA8 and SKOV3ip1), chronic restraint stress significantly increased tumor weights (182 and 315% increase, P < 0.05). This increase in tumor growth was completely blocked by Src silencing with Src siRNA-DOPC. To test the clinical significance of our biological findings, we examined 91 epithelial ovarian cancer samples. Elevated pSrcY419 was associated with worse patient survival (P < 0.001), high tumoral NE levels ( P < 0.001) and high scores on the Center for Epidemiologic Studies Depression Scale (CESD; P = 0.008). To our knowledge, this work is the first to dissect the critical molecular link between Src activation and stress-mediated cancer growth, and ultimately provide a biologically plausible and potent way of inhibiting tumor progression among patients with ovarian cancer.