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 7

Stress delays bicalutamide-induced involution and apoptosis in Hi-Myc prostates via the ADRB2/BAD pathway.

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Stress delays bicalutamide-induced involution and apoptosis in Hi-Myc pr...
Hi-Myc mice were subjected to subcutaneous injection of bicalutamide (bicalut.; 50 mg/kg, once daily) and recurrent 1-hour immobilization stress at 12-hour intervals for 3 consecutive days; blood and prostates were collected immediately after the last stress procedure. ICI118,551 was given 30 minutes before stress. (A) Stress delayed bicalutamide-induced prostate involution in Hi-Myc mice. Mouse prostates (AP, DLP, and VP lobes) were dissected and weighed, and the total prostate wet weight was expressed as mg/25 g body weight. Statistically significant differences were observed between intact and bicalutamide-treated intact Hi-Myc mice (P = 0.01) and between bicalutamide-treated intact and stressed Hi-Myc mice (P = 0.002). The effect of bicalutamide on prostate weight was completely eliminated with ICI118,551 (P = 0.54) and significantly reduced from 2- to 0.2-fold in Hi-MycBAD3SA/WT mice (P = 0.049). Representative images of prostates of Hi-Myc intact and stressed mice treated with bicalutamide are also shown. (B) Stress delayed bicalutamide-induced apoptosis in DLP glands of Hi-Myc mice (P = 0.002). The effect of stress on bicalutamide-induced apoptosis was eliminated in Hi-Myc mice injected with ICI118,551 (P = 0.84) and in compound transgenic Hi-MycBAD3SA/WT mice (P = 0.47). Representative images of cleaved caspase-3 IHC-stained sections from DLP of intact and stressed Hi-Myc mice treated with bicalutamide are also shown. Scale bars: 50 μm. Insets show the original images (×40 objective) enlarged ×2.33.