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

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

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31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)50-61
Number of pages12
JournalEBioMedicine
Volume7
DOIs
StatePublished - May 1 2016

Bibliographical note

Funding Information:
This work was supported, in part, by grants from the US National Cancer Institute ( R01 CA160333 , Y.D; R21 CA155522 , Y.D. and J.L; R01 CA172169 , J.L. and Y.D), The University of Minnesota Grant-in Aid (Y.D.) and start-up funds from The Hormel Foundation (Y.D.).

Keywords

  • 2-Deoxy-glucose
  • AMPK
  • Androgen receptor
  • Autophagy
  • Castration-resistant prostate cancer
  • Chloroquine
  • Genetically-engineered mouse model
  • Hexokinase 2
  • MCL-1
  • PTEN
  • TP53
  • ULK-1
  • Warburg effect

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