Abstract
Abstract
Behavioral stress has been long implicated in cancer pathogenesis, yet mechanistic aspects of stress/tumor interactions are understudied. Several publications described effects of stress hormone epinephrine on tumor stroma components: vasculature and immune cells; however it was not clear whether epinephrine could influence cancer cells directly and if increase of epinephrine induced by behavioral stress could activate anti-apoptotic signaling in tumors and diminish efficacy of anti-cancer therapies. Here, we studied whether subjecting mice to behavioral stress increases resistance of PTEN-deficient prostate cancer to treatments with PI3K inhibitors.
We examined effects of behavioral stress on C4-2Luc prostate cancer xenografts that express firefly luciferase and could be non-invasively monitored by luminescent imaging. In these tumor xenografts PI3K pathway is constitutively active due to the loss of PTEN expression. Injection of PI3K inhibitors into C4-2Luc xenografts induced apoptosis and substantially reduced luminescence. Subjecting mice to immobilization stress for 1 hour increased plasma epinephrine levels up to 10-15 nM, inhibited apoptosis and prevented reduction of luminescence in C4-2Luc xenografts treated with PI3K inhibitors. Injections of epinephrine had similar to stress effects. Conversely, the effect of either stress or epinephrine was completely blocked by beta2-adrenergic receptor (ADRB2) selective antagonist ICI118,551, implying that effects of stress/epinephrine are mediated via ADRB2. Elevated phosphorylation of BAD and CREB and inhibition of apoptosis was observed in xenograft tumors of mice subjected to immobilization stress. Effects of stress on BAD and CREB phosphorylation were completely blocked by ADRB2 selective antagonist ICI118,551. To test the role of protein kinase A (PKA) in anti-apoptotic signaling by stress/epinephrine in vivo we generated C4-2Luc cells that inducibly express chimera of PKA inhibitor peptide PKI and GFP (PKI-GFP). Induction of PKI-GFP expression in prostate cancer xenografts blocked stress/epinephrine-induced activation of PKA as judged by lack of CREB phosphorylation. It also prevented stress/epinephrine-induced activation of anti-apoptotic signals that phosphorylated BAD. Furthermore, C4-2Luc xenografts that inducibly express GFP-PKI were not protected from apoptosis by epinephrine or stress.
In summary, we found that subjecting mice to behavioral stress resulted in increase of serum epinephrine level leading to activation of the ADRB2 and PKA pathway in prostate tumors. This ADRB2/PKA activation is necessary for in vivo BAD phosphorylation and protection of prostate tumors from apoptosis induced by PI3K inhibitors. Thus, elevated epinephrine levels could contribute to therapy resistance of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 10. doi:10.1158/1538-7445.AM2011-10