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 6

Antiapoptotic and tumor-promoting effects of stress are eliminated in BAD3SA/WT knockin mice.

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Antiapoptotic and tumor-promoting effects of stress are eliminated in BA...
(A) Western blot analysis of DLP glands excised from 12-week-old intact and stressed Hi-MycBAD3SA/WT mice was conducted with antibodies to pCREBS133, pBADS112, cleaved caspase-3, cleaved PARP, and β-actin. (B) Densitometric analysis of Western blots revealed statistically significant increases of pCREBS133 in stressed versus intact Hi-MycBAD3SA/WT mice (P = 0.003); however, no significant differences between intact and stressed mice were found in pBADS112 (P = 0.29), cleaved caspase-3 (P = 0.47), or cleaved PARP (P = 0.25). Lysates of 4 intact mice were used for densitometry (2 mice with adrenalin levels greater than 1 nM were excluded as erroneously stressed); the stressed group contained 6 mice. (C) Prostates of intact and stressed Hi-MycBAD3SA/WT (n = 5 per group) and WTBAD3SA/WT (n = 3 per group) mice were analyzed as in Figure 3B. (D) Microphotographs of dissected prostate glands from Hi-MycBAD3SA/WT or WTBAD3SA/WT mice either subjected to repeated immobilization stress for 7 days or left intact. (E) Prostates of intact and stressed Hi-MycBAD3SA/WT mice were analyzed as in Figure 5B (n = 5 per group). Bars in B, C, and E show SD. (F) Representative images of H&E-stained sections of DLP glands of intact or stressed Hi-MycBAD3SA/WT mice. Scale bars: 50 μm.