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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Hexokinase
Castration
Autophagy
Deoxyglucose
Tumors
Prostatic Neoplasms
Chloroquine
Cells
Androgen Receptors
Apoptosis
Growth
Neoplasms
Apoptosis Regulatory Proteins
Phosphorylation
AMP-Activated Protein Kinases
Mitochondria
Heterografts
Androgens
Phase II Clinical Trials
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wang, Lei ; Wang, Ji ; Xiong, Hua ; Wu, Fengxia ; Lan, Tian ; Zhang, Yingjie ; Guo, Xiaolan ; Wang, Huanan ; Saleem, Mohammad ; Jiang, Cheng ; Lu, Junxuan ; Deng, Yibin. / Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. In: EBioMedicine. 2016 ; Vol. 7. pp. 50-61.
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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.",
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Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. / Wang, Lei; Wang, Ji; Xiong, Hua; Wu, Fengxia; Lan, Tian; Zhang, Yingjie; Guo, Xiaolan; Wang, Huanan; Saleem, Mohammad; Jiang, Cheng; Lu, Junxuan; Deng, Yibin.

In: EBioMedicine, Vol. 7, 01.05.2016, p. 50-61.

Research output: Contribution to journalArticle

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AU - Wu, Fengxia

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AU - Saleem, Mohammad

AU - Jiang, Cheng

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