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.
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Lei
L
Wang
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Ji
J
Wang
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Hua
H
Xiong
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Fengxia
F
Wu
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Tian
T
Lan
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Yingjie
Y
Zhang
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Xiaolan
X
Guo
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Huanan
H
Wang
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA.
Mohammad
M
Saleem
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA.
Cheng
C
Jiang
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USA.
Junxuan
J
Lu
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USA. Electronic address: yideng@hi.umn.edu.
Yibin
Y
Deng
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000037:antagonists & inhibitors; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000008:administration & dosage* / Q000494:pharmacology; D003847:Deoxyglucose / Q000008:administration & dosage* / Q000494:pharmacology; D006593:Hexokinase / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D009570:Nitriles; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010669:Phenylthiohydantoin; D002738:Chloroquine; C540278:enzalutamide; D003847:Deoxyglucose; D006593:Hexokinase; D000071189:Autophagy-Related Protein-1 Homolog; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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