Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway

Oncogene volume 37, pages 2953–2966 (2018)Cite this article

Subjects

Abstract

Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Mehta RD, Roth AJ. Psychiatric considerations in the oncology setting. CA Cancer J Clin. 2015;65:300–14.

    Article  PubMed  Google Scholar 

  2. Lopez-Calderero I, Lopez-Fando L, Rios-Gonzalez E, Maisonobe P, Hernandez-Yuste E, Sarmiento-Jordan M. Impact of locally advanced or metastatic prostate cancer on the quality of life. Actas Urol Esp. 2017;41:368–75.

    Article  CAS  PubMed  Google Scholar 

  3. Prasad SM, Eggener SE, Lipsitz SR, Irwin MR, Ganz PA, Hu JC. Effect of depression on diagnosis, treatment, and mortality of men with clinically localized prostate cancer. J Clin Oncol. 2014;32:2471–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Batty GD, Russ TC, Stamatakis E, Kivimaki M. Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies. BMJ 2017;356:j108.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sullivan DR, Forsberg CW, Ganzini L, Au DH, Gould MK, Provenzale D, et al. Longitudinal changes in depression symptoms and survival among patients with lung cancer: a national cohort assessment. J Clin Oncol. 2016;34:3984–91.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341:1236361.

    Article  PubMed  Google Scholar 

  7. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res. 2008;14:7593–603.

    Article  CAS  PubMed  Google Scholar 

  8. Lu D, Sinnott JA, Valdimarsdottir U, Fang F, Gerke T, Tyekucheva S, et al. Stress-related signaling pathways in lethal and nonlethal prostate cancer. Clin Cancer Res. 2016;22:765–72.

    Article  CAS  PubMed  Google Scholar 

  9. Kupfer DJ, Frank E, Phillips ML. Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet. 2012;379:1045–55.

    Article  PubMed  Google Scholar 

  10. Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Harryman WL, Hinton JP, Rubenstein CP, Singh P, Nagle RB, Parker SJ, et al. The cohesive metastasis phenotype in human prostate cancer. Biochim Biophys Acta. 2016;1866:221–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Gaston SM, Soares MA, Siddiqui MM, Vu D, Lee JM, Goldner DL, et al. Tissue-print and print-phoresis as platform technologies for the molecular analysis of human surgical specimens: mapping tumor invasion of the prostate capsule. Nat Med. 2005;11:95–101.

    Article  CAS  PubMed  Google Scholar 

  13. de la Taille A, Rubin MA, Buttyan R, Olsson CA, Bagiella E, Burchardt M, et al. Is microvascular invasion on radical prostatectomy specimens a useful predictor of PSA recurrence for prostate cancer patients? Eur Urol. 2000;38:79–84.

    Article  PubMed  Google Scholar 

  14. Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 2015;33:230–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ko CJ, Huang CC, Lin HY, Juan CP, Lan SW, Shyu HY, et al. Androgen-induced TMPRSS2 activates matriptase and promotes extracellular matrix degradation, prostate cancer cell invasion, tumor growth, and metastasis. Cancer Res. 2015;75:2949–60.

    Article  CAS  PubMed  Google Scholar 

  16. Mo F, Lin D, Takhar M, Ramnarine VR, Dong X, Bell RH, et al. Stromal gene expression is predictive for metastatic primary prostate cancer. Eur Urol. 2017:e-pub ahead of print 2017; doi:2010.1016/j.eururo.2017.2002.2038.

  17. Nader GP, Ezratty EJ, Gundersen GG. FAK, talin and PIPKIgamma regulate endocytosed integrin activation to polarize focal adhesion assembly. Nat Cell Biol. 2016;18:491–503.

    Article  CAS  PubMed  Google Scholar 

  18. Slack-Davis JK, Hershey ED, Theodorescu D, Frierson HF, Parsons JT. Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol Cancer Ther. 2009;8:2470–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Feng Y, Huang W, Tian TF, Wang G, Hu C, Chiu HF, et al. The psychometric properties of the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) and the Patient Health Questionnaire-9 (PHQ-9) in depressed inpatients in China. Psychiatry Res. 2016;243:92–6.

    Article  PubMed  Google Scholar 

  20. Furukawa TA. Assessment of mood: guides for clinicians. J Psychosom Res. 2010;68:581–9.

    Article  PubMed  Google Scholar 

  21. Katz RJ. Animal model of depression: pharmacological sensitivity of a hedonic deficit. Pharmacol, Biochem, Behav. 1982;16:965–8.

    Article  CAS  Google Scholar 

  22. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology. 1987;93:358–64.

    Article  CAS  PubMed  Google Scholar 

  23. Hill MN, Hellemans KG, Verma P, Gorzalka BB, Weinberg J. Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev. 2012;36:2085–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cole SW, Sood AK. Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res. 2012;18:1201–6.

    Article  CAS  PubMed  Google Scholar 

  25. Barbieri A, Bimonte S, Palma G, Luciano A, Rea D, Giudice A, et al. The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. Int J Oncol. 2015;47:527–34.

    Article  CAS  PubMed  Google Scholar 

  26. Lopez-Colome AM, Lee-Rivera I, Benavides-Hidalgo R, Lopez E. Paxillin: a crossroad in pathological cell migration. J Hematol Oncol. 2017;10:50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Law NC, Donaubauer EM, Zeleznik AJ, Hunzicker-Dunn M. How protein kinase A activates canonical tyrosine kinase signaling pathways to promote granulosa cell differentiation. Endocrinology. 2017;158:2043–51.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Piiper A, Lutz MP, Cramer H, Elez R, Kronenberger B, Dikic I, et al. Protein kinase A mediates cAMP-induced tyrosine phosphorylation of the epidermal growth factor receptor. Biochem Biophys Res Commun. 2003;301:848–54.

    Article  CAS  PubMed  Google Scholar 

  29. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129–36.

    Article  CAS  PubMed  Google Scholar 

  30. Hassan S, Karpova Y, Baiz D, Yancey D, Pullikuth A, Flores A, et al. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. 2013;123:874–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Le CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun. 2016;7:10634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer. 2014;14:598–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jin JK, Tien PC, Cheng CJ, Song JH, Huang C, Lin SH, et al. Talin1 phosphorylation activates beta1 integrins: a novel mechanism to promote prostate cancer bone metastasis. Oncogene. 2015;34:1811–21.

    Article  CAS  PubMed  Google Scholar 

  34. Sood AK, Armaiz-Pena GN, Halder J, Nick AM, Stone RL, Hu W, et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest. 2010;120:1515–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ma X, Zhao Y, Daaka Y, Nie Z. Acute activation of beta2-adrenergic receptor regulates focal adhesions through betaArrestin2- and p115RhoGEF protein-mediated activation of RhoA. J Biol Chem. 2012;287:18925–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017;20:156–66.

    Article  CAS  PubMed  Google Scholar 

  37. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–51.

    Article  CAS  PubMed  Google Scholar 

  38. Madden KS. Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. Dev Comp Immunol. 2017;66:92–7.

    Article  CAS  PubMed  Google Scholar 

  39. Qin J-f, Jin F-j, Li N, Guan H-t, Lan L, Ni H. et al. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 2015;48:295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.

    Article  CAS  PubMed  Google Scholar 

  41. Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 2016;6:852–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Uehara A, Motegi S, Yamada K, Uchiyama A, Perera B, Toki S, et al. Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis. Sci Rep. 2016;6:34012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med. 2014;6:250ra115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Batkin S, Piette LH, Wildman E. Effect of muscle denervation on growth of transplanted tumor in mice. Proc Natl Acad Sci USA. 1970;67:1521–7.

    Article  CAS  PubMed  Google Scholar 

  45. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev. 2010;21:77–82.

    Article  CAS  PubMed  Google Scholar 

  46. Venkatesh H, Monje M. Neuronal activity in ontogeny and oncology. Trends Cancer. 2017;3:89–112.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–29.

    Article  CAS  PubMed  Google Scholar 

  48. Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Venkitaraman R, Lorente D, Murthy V, Thomas K, Parker L, Ahiabor R, et al. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015;67:673–9.

    Article  CAS  PubMed  Google Scholar 

  50. Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23:554–62.

    Article  CAS  PubMed  Google Scholar 

  51. Dimitrov S, Lange T, Born J. Selective mobilization of cytotoxic leukocytes by epinephrine. J Immunol. 2010;184:503–11.

    Article  CAS  PubMed  Google Scholar 

  52. Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014;159:33–45.

    Article  CAS  PubMed  Google Scholar 

  53. Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003;4:223–38.

    Article  CAS  PubMed  Google Scholar 

  54. Mao J, Wang D, Wang Z, Tian W, Li X, Duan J, et al. Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/beta-catenin pathway. Cancer Lett. 2016;380:134–43.

    Article  CAS  PubMed  Google Scholar 

  55. Li X, Wang D, Chen Z, Lu E, Wang Z, Duan J, et al. Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1. Proc Natl Acad Sci USA. 2015;112:4731–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Mrs. Ning Su for IHC studies, Mrs. Jian-hua Ding for HPLC studies, and Dr. Wen-tao Liu for gelatin zymography experiments and helpful suggestions. This study was supported by grants from Intramural Research Program of the NIH (Z01-ES101684 to LB), The 111 Project (No.111-2-07), National Science Foundation of China (91529304, 81673468 to YY, 81603132 to XG and 81403020 to LY), Natural Science Foundation of Jiangsu Province (No. BK20160753 to XG), and China Postdoctoral Science Foundation (No. 2016M591965 to XG).

Author information

Author notes

  1. These authors contributed equally: Yan Cheng, Xing-Hua Gao, Xian-Jing Li.

  2. These authors jointly supervised this work: Lutz Birnbaumer, Yong Yang.

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China

    Yan Cheng, Xing-Hua Gao, Xian-Jing Li, Qiu-Hua Cao, Dan-Dan Zhao, Hong-Xi Wu, Yun Wang, Lin-Jun You, Hong-Bao Yang, Yun-Long He, Yong-Ren Li & Yong Yang

  2. Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02138, USA

    Jin-Rong Zhou

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Jin-Song Bian

  4. Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, 210029, China

    Qing-Yi Zhu

  5. Neurobiology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, 27709, USA

    Lutz Birnbaumer

  6. Biomedical Research Institute,(BOMED), Catholic University of Argentina, Buenos Aires, C1107AAZ, Argentina

    Lutz Birnbaumer

Authors
  1. Yan Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xing-Hua Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xian-Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiu-Hua Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan-Dan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Rong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong-Xi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lin-Jun You
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hong-Bao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yun-Long He
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yong-Ren Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jin-Song Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Qing-Yi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lutz Birnbaumer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lutz Birnbaumer or Yong Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, Y., Gao, XH., Li, XJ. et al. Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway. Oncogene 37, 2953–2966 (2018). https://doi.org/10.1038/s41388-018-0177-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0177-4

This article is cited by

Search

Advanced search

Quick links