Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer.

Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten-/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations.

EBioMedicine. 2016 Mar 19 [Epub]

Lei Wang, Ji Wang, Hua Xiong, Fengxia Wu, Tian Lan, Yingjie Zhang, Xiaolan Guo, Huanan Wang, Mohammad Saleem, Cheng Jiang, Junxuan Lu, Yibin Deng

Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA., Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA., Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA., Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA. Electronic address: .

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