Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer.

Prostate cancer is characterized by a dependence upon androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) is the accepted treatment for progressive prostate cancer. Although ADT is usually initially effective, acquired resistance termed castrate-resistant prostate cancer (CRPC) develops. PTEN and TP53 are two of the most commonly deleted or mutated genes in prostate cancer, the compound loss of which is enriched in CRPC. To interrogate the metabolic alterations associated with survival following ADT, we used an orthotopic model of Pten/Tp53 null prostate cancer. Metabolite profiles and associated regulators were compared in tumors from androgen-intact mice and in tumors surviving castration. AR inhibition led to changes in the levels of glycolysis and tricarboxylic acid (TCA) cycle pathway intermediates. As anticipated for inhibitory reciprocal feedback between AR and PI3K/AKT signaling pathways, pAKT levels were increased in androgen-deprived tumors. Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association. Competitive inhibition of HK2-mitochondrial binding in prostate cancer cells led to decreased viability. These data argue for AKT-associated HK2-mediated metabolic reprogramming and mitochondrial association in PI3K-driven prostate cancer as one survival mechanism downstream of AR inhibition.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.223.

Oncogene. 2016 Jul 04 [Epub ahead of print]

P L Martin, J-J Yin, V Seng, O Casey, E Corey, C Morrissey, R M Simpson, K Kelly

Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Department of Urology, University of Washington, Seattle, WA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.