Behavioral stress accelerates prostate cancer development in mice
Sazzad Hassan, … , Sandeep Robert Datta, George Kulik
Sazzad Hassan, … , Sandeep Robert Datta, George Kulik
Published February 1, 2013; First published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):874-886. https://doi.org/10.1172/JCI63324.
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Research Article

Behavioral stress accelerates prostate cancer development in mice

Abstract

Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress–prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog–deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling.

Authors

Sazzad Hassan, Yelena Karpova, Daniele Baiz, Dana Yancey, Ashok Pullikuth, Anabel Flores, Thomas Register, J. Mark Cline, Ralph D’Agostino Jr., Nika Danial, Sandeep Robert Datta, George Kulik

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Figure 4

Stress induces BAD phosphorylation and inhibits cleavage of PARP and caspase-3 in Hi-Myc mouse prostate glands.

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Stress induces BAD phosphorylation and inhibits cleavage of PARP and cas...
WT and Hi-Myc mice were subjected to recurrent 1-hour immobilization stress at 12-hour intervals for 7 consecutive days; blood and prostates were collected immediately after the last stress procedure. ICI118,551 was given 30 minutes before stress. (A) Western blot analysis of DLP glands excised from intact (denoted “calm” or “C”) and stressed (“stress” or “S”) mice was conducted with antibodies to pCREBS133, pBADS112, cleaved caspase-3, cleaved PARP, α-tubulin, and c-Myc. 4 representative samples from each treatment group are shown. (B) Densitometric analysis of Western blots revealed statistically significant increases of BAD and CREB phosphorylation in stressed versus intact mice (pBADS112, P = 0.005 between WT groups; P = 0.02 between Hi-Myc groups; pCREBS133, P = 0.02 between WT groups; P = 0.0019 between Hi-Myc groups) and reduced cleavage of caspase-3 (P = 0.005) and PARP (P = 0.01) in stressed versus intact Hi-Myc mice. These effects of stress were completely eliminated by ICI118,551. Each experimental group contained at least 5 mice. Error bars represent SD from the average of at least 5 samples.