Abstract SY04-01: Behavioral stress protects prostate cancer cells from apoptosis

Behavioral stress has been long implicated in cancer pathogenesis, yet mechanistic aspects of stress/tumor interactions are understudied. Several recent publications described effects of stress hormone epinephrine on tumor stroma components: vasculature and immune cells (Lutgendorf 2010; Sloan 2010; Thaker 2006); however, it was not clear whether epinephrine could influence cancer cells directly. Earlier we reported that epinephrine inhibits apoptosis in prostate cancer cells in tissue culture (Sastry 2007). It was unknown, however, if increase of epinephrine observed during behavioral stress could activate antiapoptotic signaling in prostate tumors and diminish efficacy of anticancer therapies. We will present evidence that subjecting mice to behavioral stress increases resistance of PTEN-deficient C42Luc prostate cancer xenografts to treatments with PI3K inhibitors. PI3K inhibitors induced apoptosis in prostate cancer xenografts; while subjecting mice to stress at the time of administration of PI3K inhibitors significantly reduces tumor cell loss. Effects of behavioral stress are mediated by epinephrine that inhibits apoptosis in prostate cancer xenografts. Antiapoptotic effects of stress/epinephrine are mediated via β2-adrenergic receptor (β2AR) and cAMP-dependent protein kinase (PKA) pathway, which in turn induced phosphorylation of BH3-only protein BAD. This study has following novel aspects: 1) It is a first report on activation of β2AR/PKA/BAD antiapoptotic pathway in tumors in vivo. 2) It is a first report that demonstrates effect of behavioral stress on therapy resistance of prostate tumors in mouse models. Information on antiapoptotic signaling by β2AR/PKA/BAD pathway activated by stress levels of epinephrine establishes a foundation for clinical trials that examine effects of stress reduction and/or administration of β2AR-antagonists on treatment efficacy in prostate cancer patients. References: 1. Lutgendorf SK, Sood AK, Antoni MH. Host factors and cancer progression: biobehavioral signaling pathways and interventions. J Clin Oncol. 2010 Sep10;28(26):4094-9. 2. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010 Sep 15;70(18):7042-52. 3. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006 Aug;12(8):939-44. 4. Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A, Carson JP, Weber MJ, Register TC, Chen YQ, Penn RB, Kulik G. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J Biol Chem. 2007 May 11;282(19):14094-100 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 SY04-01. doi:10.1158/1538-7445.AM2011-SY04-01