Behavioral stress accelerates prostate cancer development in mice
Sazzad Hassan, … , Sandeep Robert Datta, George Kulik
Sazzad Hassan, … , Sandeep Robert Datta, George Kulik
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 1

Stress or adrenaline prevents apoptosis induced by PI3K inhibitor in prostate cancer xenografts.

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Stress or adrenaline prevents apoptosis induced by PI3K inhibitor in pro...
(A) Representative images of mice with C42LucBAD xenografts. Mice were injected with DMSO, ZSTK474 (ZSTK), or ZSTK474 followed by immobilization stress. Luminescence of xenograft tumors was measured before injection of PI3K inhibitors (0 hour) and after injections at 24 and 72 hours. (B) Immunohistochemical analysis of cleaved caspase-3 in C42LucBAD xenograft tumors. Mice were treated as in A, and xenografts were excised 6 hours after injections. Scale bars: 50 μm. (C) Dynamics of luminescence in C42LucBAD xenograft tumors. Mice were injected with DMSO (n = 3), ZSTK474 (n = 3), ZSTK474 followed by immobilization stress (n = 3), ZSTK474 and adrenaline (adren; n = 3), ZSTK474 and ICI118,551 (ICI) followed by immobilization stress (n = 3), or ZSTK474, ICI118,551, and adrenaline (n = 4). Error bars show SD from the average of measurements in at least 3 mice. Comparisons between pairs of groups were performed using t tests derived from the overall ANOVA model. Significant between-group differences over time were as follows: P < 0.02, ZSTK vs. DMSO; P < 0.01, ZSTK+stress vs. ZSTK; P < 0.03, ZSTK+adren vs. ZSTK; P < 0.003, ZSTK+ICI+stress vs. ZSTK+stress; P < 0.006, ZSTK+ICI+adren vs. ZSTK+adren. (D) Western blot analysis of C42LucBAD xenograft tumor tissues excised 6 hours after injection of ZSTK474 and/or ICI118,551 (ICI) into mice that were then subjected to immobilization stress, left intact, or injected with epinephrine. At the time of xenograft excision, blood was collected for adrenaline measurements (shown above blots).