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

Abstract

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.

• Authors: Lei Wang, Ji Wang, Hua Xiong, Fengxia Wu, Tian Lan, Yingjie Zhang, Xiaolan Guo, Huanan Wang, Mohammad Saleem, Cheng Jiang, Junxuan Lu, Yibin Deng
• Journal: EBioMedicine (EBioMedicine) Vol. 7 Pg. 50-61 (May 2016) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 27322458 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• Nitriles
• TP53 protein, human
• Tumor Suppressor Protein p53
• Phenylthiohydantoin
• Chloroquine
• enzalutamide
• Deoxyglucose
• Hexokinase
• Autophagy-Related Protein-1 Homolog
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Autophagy (drug effects)
• Autophagy-Related Protein-1 Homolog (antagonists & inhibitors)
• Benzamides
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chloroquine (administration & dosage, pharmacology)
• Deoxyglucose (administration & dosage, pharmacology)
• Hexokinase (antagonists & inhibitors)
• Humans
• Male
• Mice
• Nitriles
• PTEN Phosphohydrolase (deficiency)
• Phenylthiohydantoin (analogs & derivatives)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (deficiency)
• Xenograft Model Antitumor Assays