Behavioral Stress Accelerates Prostate Cancer Development in Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2013 Jan 26

PMID 23348742

Citations 145

Authors

Sazzad Hassan

Yelena Karpova

Daniele Baiz

Dana Yancey

Ashok Pullikuth

Anabel Flores

Thomas Register

J Mark Cline

Ralph DAgostino Jr

Nika Danial

Sandeep Robert Datta

George Kulik

Affiliations

Soon will be listed here.

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.

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References

Harada H, Becknell B, Wilm M, Mann M, Huang L, Taylor S . Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell. 1999; 3(4):413-22. DOI: 10.1016/s1097-2765(00)80469-4. View

Thaker P, Sood A . Neuroendocrine influences on cancer biology. Semin Cancer Biol. 2008; 18(3):164-70. PMC: 2424028. DOI: 10.1016/j.semcancer.2007.12.005. View

Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver B . Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18(1):11-22. PMC: 3198787. DOI: 10.1016/j.ccr.2010.05.026. View

Nagmani R, Pasco D, Salas R, Feller D . Evaluation of beta-adrenergic receptor subtypes in the human prostate cancer cell line-LNCaP. Biochem Pharmacol. 2003; 65(9):1489-94. DOI: 10.1016/s0006-2952(03)00105-9. View

Kulik G, Klippel A, Weber M . Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997; 17(3):1595-606. PMC: 231885. DOI: 10.1128/MCB.17.3.1595. View

Yemelyanov A, Czwornog J, Chebotaev D, Karseladze A, Kulevitch E, Yang X . Tumor suppressor activity of glucocorticoid receptor in the prostate. Oncogene. 2006; 26(13):1885-96. DOI: 10.1038/sj.onc.1209991. View

Baiz D, Pinder T, Hassan S, Karpova Y, Salsbury F, Welker M . Synthesis and characterization of a novel prostate cancer-targeted phosphatidylinositol-3-kinase inhibitor prodrug. J Med Chem. 2012; 55(18):8038-46. PMC: 3738169. DOI: 10.1021/jm300881a. View

Cao L, Liu X, Lin E, Wang C, Choi E, Riban V . Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell. 2010; 142(1):52-64. PMC: 3784009. DOI: 10.1016/j.cell.2010.05.029. View

Feng Z, Liu L, Zhang C, Zheng T, Wang J, Lin M . Chronic restraint stress attenuates p53 function and promotes tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109(18):7013-8. PMC: 3345015. DOI: 10.1073/pnas.1203930109. View

10.

Parker J, Klein S, McClintock M, Morison W, Ye X, Conti C . Chronic stress accelerates ultraviolet-induced cutaneous carcinogenesis. J Am Acad Dermatol. 2004; 51(6):919-22. DOI: 10.1016/j.jaad.2004.08.042. View

11.

Zha J, Harada H, Yang E, Jockel J, Korsmeyer S . Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 1996; 87(4):619-28. DOI: 10.1016/s0092-8674(00)81382-3. View

12.

Grytli H, Fagerland M, Fossa S, Tasken K, Haheim L . Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate. 2012; 73(3):250-60. DOI: 10.1002/pros.22564. View

13.

Armaiz-Pena G, Lutgendorf S, Cole S, Sood A . Neuroendocrine modulation of cancer progression. Brain Behav Immun. 2008; 23(1):10-5. PMC: 2630522. DOI: 10.1016/j.bbi.2008.06.007. View

14.

Blok L, de Ruiter P, Brinkmann A . Forskolin-induced dephosphorylation of the androgen receptor impairs ligand binding. Biochemistry. 1998; 37(11):3850-7. DOI: 10.1021/bi9724422. View

15.

Gousse A, Yoshida M, Weiss R, Latifpour J . Beta adrenergic receptor alterations in diabetic rat prostate: effects of insulin and dietary myoinositol. Prostate. 1991; 19(2):121-31. DOI: 10.1002/pros.2990190205. View

16.

Fu M, Rao M, Wu K, Wang C, Zhang X, Hessien M . The androgen receptor acetylation site regulates cAMP and AKT but not ERK-induced activity. J Biol Chem. 2004; 279(28):29436-49. DOI: 10.1074/jbc.M313466200. View

17.

Ramberg H, Eide T, Krobert K, Levy F, Dizeyi N, Bjartell A . Hormonal regulation of beta2-adrenergic receptor level in prostate cancer. Prostate. 2008; 68(10):1133-42. DOI: 10.1002/pros.20778. View

18.

Massie M . Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004; (32):57-71. DOI: 10.1093/jncimonographs/lgh014. View

19.

Scattoni V, Montironi R, Mazzucchelli R, Freschi M, Nava L, Losa A . Pathological changes of high-grade prostatic intraepithelial neoplasia and prostate cancer after monotherapy with bicalutamide 150 mg. BJU Int. 2006; 98(1):54-8. DOI: 10.1111/j.1464-410X.2006.06204.x. View

20.

Sood A, Armaiz-Pena G, Halder J, Nick A, Stone R, Hu W . Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest. 2010; 120(5):1515-23. PMC: 2860925. DOI: 10.1172/JCI40802. View