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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

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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 3

Activation of pBADS112 is necessary for stress- or adrenaline-induced protection from apoptosis in prostate cancer xenografts.

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Activation of pBADS112 is necessary for stress- or adrenaline-induced pr...
(A) Analysis of C42LucBAD1SA xenograft tumors by Western blotting. ZSTK474 inhibited pAktS473 and pBADS112 and induced cleavage of PARP and caspase-3. Stress or adrenaline induced pBADS112 and pCREBS133 and inhibited cleavage of PARP and caspase-3. Effects of stress or adrenaline on apoptosis (cleavage of caspase-3 and PARP) were blocked by doxycycline-induced expression of mutant HA-BADS112A. Arrowheads denote HA-BAD1SA (top) and endogenous BAD (bottom). The inset at right from a pBAD blot shows lysates of C42LucBAD cells that served as positive control for phosphorylated HA-BAD. Mutant HA-BADS112A (lanes 5–7) could not be phosphorylated and was not recognized by pBADS112-specific antibodies. (B and C) Effects of stress or adrenaline on tumor luminescence depend on pBADS112. (B) In mice that did not receive doxycycline, luminescence in ZSTK+stress and ZSTK+adren groups was highly significantly different compared with the ZSTK group (P < 0.0001 for both). (C) These differences were completely eliminated by doxycycline-induced expression of pBADS112-deficient HA-BAD1SA (P > 0.65 and P > 0.52, respectively). Error bars in B and C show the SD from the average of measurements in at least 4 mice.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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