title: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1alpha levels contribute to emergence of an aggressive phenotype in prostate cancer.
abstract: Androgen receptor (AR) signaling is involved in the development and progression of prostate cancer. Tumor microvasculature contributes to continual exposure of prostate cancer cells to hypoxia-reoxygenation, however, the role of hypoxia-reoxygenation in prostate cancer progression and modulation of AR signaling is not understood. In this study, we evaluated the effects of hypoxia-reoxygenation in LNCaP cells, a line of hormone responsive human prostate cancer cells. Our results demonstrate that hypoxia-reoxygenation resulted in increased survival, higher clonogenicity and enhanced invasiveness of these cells. Moreover, hypoxia-reoxygenation was associated with an increased AR activity independent of androgens as well as increased hypoxia inducible factor (HIF-1alpha) levels and activity. We also observed that the activation of p38 mitogen-activated protein (MAP) kinase pathway was an early response to hypoxia, and inhibition of p38 MAP kinase pathway by variety of approaches abolished hypoxia-reoxygenation induced increased AR activity as well as increased survival, clonogenicity and invasiveness. These results demonstrate a critical role for hypoxia-induced p38 MAP kinase pathway in androgen-independent AR activation in prostate cancer cells, and suggest that hypoxia-reoxygenation may select for aggressive androgen-independent prostate cancer phenotype.
authors.affiliation: Signal Transduction and Molecular Urology Laboratory-Program in Urosciences, Division of Urology, Department of Surgery, School of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: L
authors.initials: L
authors.lastname: Khandrika
authors.forename: R
authors.initials: R
authors.lastname: Lieberman
authors.forename: S
authors.initials: S
authors.lastname: Koul
authors.forename: B
authors.initials: B
authors.lastname: Kumar
authors.forename: P
authors.initials: P
authors.lastname: Maroni
authors.forename: R
authors.initials: R
authors.lastname: Chandhoke
authors.forename: R B
authors.initials: RB
authors.lastname: Meacham
authors.forename: H K
authors.initials: HK
authors.lastname: Koul
mesh_terms: D000728:Androgens; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000728:Androgens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048051:p38 Mitogen-Activated Protein Kinases