A growing number of studies indicate that chronic stress can accelerate tumor growth due to sustained sympathetic nervous system activation. Our recent findings suggest that chronic stress is associated with increased IL8 levels. Here, we examined the molecular and biological significance of IL8 in stress-induced tumor growth. Norepinephrine (NE) treatment of ovarian cancer cells resulted in a 250–300% increase in IL8 protein and 240–320% increase in its mRNA levels. Epinephrine treatment resulted in similar increases. Moreover, NE treatment resulted in a 3.5–4-fold increase in IL8 promoter activity. These effects were blocked by propranolol. Promoter deletion analyses suggested that AP1 transcription factors might mediate catecholamine-stimulated up-regulation of IL8. siRNA inhibition studies identified FosB as the pivotal component responsible for IL8 regulation by NE. In vivo chronic stress resulted in increased tumor growth (by 221 and 235%; p < 0.01) in orthotopic xenograft models involving SKOV3ip1 and HeyA8 ovarian carcinoma cells. This enhanced tumor growth was completely blocked by IL8 or FosB gene silencing using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes. IL8 and FosB silencing reduced microvessel density (based on CD31 staining) by 2.5- and 3.5-fold, respectively (p < 0.001). Our findings indicate that neurobehavioral stress leads to FosB-driven increases in IL8, which is associated with increased tumor growth and metastases. These findings may have implications for ovarian cancer management.
This work was supported, in whole or in part, by National Institutes of Health Grants CA109298, CA110793, CA128797, RC2GM092599, and CA151668. This work was also supported by a program project development grant from the Ovarian Cancer Research Fund, Inc., the Zarrow Foundation, the Marcus Foundation, a grant from the Alliance for Nanohealth, the Meyer and Ida Gordon Foundation Number 2, Department of Defense Grants OC073399 and W81XWH-10-1-0158, the University of Texas M.D. Anderson Cancer Center SPORE in Ovarian Cancer Grant P50 CA083639, and the Blanton-Davis Ovarian Cancer Research Program.
Supported by National Institutes of Health Scholarship Grant HD050128 from NICHD, Baylor Women Reproductive Health Research Program, and the Gynecologic Cancer Foundation Molly-Cade ovarian cancer research grant.
Supported in part by NCI-DHHS National Institutes of Health T32 Training Grant T32 CA101642 and T32 CA009614 from NCI-Department of Health and Human Services.
