title: The interplay of AMP-activated protein kinase and androgen receptor in prostate cancer cells.
abstract: AMP-activated protein kinase (AMPK) has recently emerged as a potential target for cancer therapy due to the observation that activation of AMPK inhibits tumor cell growth. It is well-known that androgen receptor (AR) signaling is a major driver for the development and progression of prostate cancer and that downregulation of AR is a critical step in the induction of apoptosis in prostate cancer cells. However, little is known about the potential interaction between AMPK and AR signaling pathways. In the current study, we showed that activation of AMPK by metformin caused decrease of AR protein level through suppression of AR mRNA expression and promotion of AR protein degradation, demonstrating that AMPK activation is upstream of AR downregulation. We also showed that inhibition of AR function by an anti-androgen or its siRNA enhanced AMPK activation and growth inhibition whereas overexpression of AR delayed AMPK activation and increased prostate cancer cellular resistance to metformin treatment, suggesting that AR suppresses AMPK signaling-mediated growth inhibition in a feedback mechanism. Our findings thus reveal a novel AMPK-AR regulatory loop in prostate cancer cells and should have a potential clinical significance.
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan; Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Manohar
authors.initials: M
authors.lastname: Ratnam
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D008687:Metformin; C053541:bicalutamide; D055372:AMP-Activated Protein Kinases