Behavioral stress accelerates prostate cancer development in mice
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
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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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 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.