title: Ion channel TRPM8 promotes hypoxic growth of prostate cancer cells via an O2 -independent and RACK1-mediated mechanism of HIF-1α stabilization.
abstract: The growth adaptation of cancer cells to a hypoxic tumour microenvironment is mostly regulated by hypoxia-induced transcription factor HIF-1. HIF-1 transcriptional activity is strictly controlled by protein levels of the HIF-1α subunit, which is tightly regulated by a well-characterized O2 -dependent ubiquitin ligase-proteasomal degradation pathway. The cold-sensitive Ca(2+) channel protein TRPM8 exhibits increased expression in advanced prostate cancer. However, its exact functional roles in prostate cancer growth regulation are unclear and controversial. In this work, we show that TRPM8 promotes in vitro hypoxic growth capacities, drug resistance, and in vivo tumourigenicity, accompanied with enhanced HIF-1α protein levels. These effects are further potentiated by TRPM8 agonists but suppressed by TRPM8 gene knockdown and blocking with antagonists or TRPM8 antibody. TRPM8-induced suppression of HIF-1α ubiquitination and enhanced HIF-1 transactivation were attenuated by forced RACK1 expression and TRPM8 overexpression reduced phospho-RACK1 levels, thus affecting its dimerization status, and promoted RACK1 binding to HIF-1α and calcineurin. These data indicate that TRPM8-induced increase of HIF-1α protein in hypoxia- or normoxia-exposed prostate cancer cells was mediated through a newly characterized Ca(2+) -dependent but O2 -independent mechanism involving binding of RACK1 to HIF-1α and RACK1-mediated ubiquitination of HIF-1α. Collectively, our study not only provides a mechanistic insight into how TRPM8 promotes the hypoxic growth adaptation of cancer cells via its promotion of RACK1-mediated stabilization of HIF-1α but also suggests a potential therapeutic strategy for prostate cancer by targeting TRPM8.
authors: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors: Shan
authors: S
authors: Yu
authors: Zhenyu
authors: Z
authors: Xu
authors: Chang
authors: C
authors: Zou
authors: Dinglan
authors: D
authors: Wu
authors: Yuliang
authors: Y
authors: Wang
authors: Xiaoqiang
authors: X
authors: Yao
authors: Chi-Fai
authors: CF
authors: Ng
authors: Franky L
authors: FL
authors: Chan
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D019204:GTP-Binding Proteins; D010100:Oxygen
keywords: HIF-1α; RACK1; hypoxia; prostate cancer; transient receptor potential channel; ubiquitination