Activin A Enhances Prostate Cancer Cell Migration Through Activation of Androgen Receptor and Is Overexpressed in Metastatic Prostate Cancer

Authors

  • Hong-Yo Kang,

    Corresponding author
    1. Graduate Institute of Clinical Medical Sciences, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    2. Center for Menopause and Reproductive Research, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    • Address correspondence to: Hong-Yo Kang, PhD, Graduate Institute of Clinical Medical Sciences, and Ko-Zn Huang, MD, Center for Menopause and Reproductive Research, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan
    Search for more papers by this author
  • Hsuan-Ying Huang,

    1. Department of Pathology, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    Search for more papers by this author
  • Chang-Yi Hsieh,

    1. Center for Menopause and Reproductive Research, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    Search for more papers by this author
  • Chien-Feng Li,

    1. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
    Search for more papers by this author
  • Chih-Rong Shyr,

    1. Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualian, Taiwan
    Search for more papers by this author
  • Meng-Yin Tsai,

    1. Obstetrics and Gynecology, University of Rochester, Rochester, New York, USA
    Search for more papers by this author
  • Chawnshang Chang,

    1. Department of Pathology and Urology, University of Rochester, Rochester, New York, USA
    Search for more papers by this author
  • Yao-Chi Chuang,

    1. Department of Urology, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    Search for more papers by this author
  • Ko-En Huang

    1. Center for Menopause and Reproductive Research, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan
    2. Obstetrics and Gynecology, University of Rochester, Rochester, New York, USA
    Search for more papers by this author

  • The authors state that they have no conflicts of interest

  • Published online on February 16, 2009

Abstract

Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A–promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A–mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A–promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A–Smad–AR axis may be considered a therapeutic target in bone metastatic diseases.

Ancillary