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 5

Stress accelerates PIN growth and inhibits apoptosis in DLP glands of Hi-Myc mice.

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Stress accelerates PIN growth and inhibits apoptosis in DLP glands of Hi...
(A) Stress increased prostate weight. 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 stressed Hi-Myc mice (P = 0.002), but not between WT groups (P = 1.00). This difference in Hi-Myc mice was eliminated by ICI118,551 injection prior to stress (P = 0.49). (B) Stress reduced apoptosis in DLP glands. Percent cleaved caspase-3–labeled cells in immunostained sections was determined relative to the total number of glandular epithelial cells in whole sections of DLP. Representative images of cleaved caspase-3 IHC-stained sections from DLP of intact or stressed Hi-Myc mice are also shown. Scale bars: 50 μm. Insets show the original images (×40 objective) enlarged ×5. (C) Stress increased PIN in DLP glands of Hi-Myc mice. Percent PIN area was determined as area of PIN divided by total DLP glandular area. Representative microphotographs of H&E-stained sections from DLP glands of intact and stressed Hi-Myc mice are also shown. Scale bars: 50 μm. See Supplemental Figure 8D for morphology of mouse PIN. Error bars in A–C show SD from the average of at least 5 samples.