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 CRP...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-05-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396416301098 |
| _version_ | 1818675182156382208 |
|---|---|
| author | Lei Wang Ji Wang Hua Xiong Fengxia Wu Tian Lan Yingjie Zhang Xiaolan Guo Huanan Wang Mohammad Saleem Cheng Jiang Junxuan Lu Yibin Deng |
| author_facet | Lei Wang Ji Wang Hua Xiong Fengxia Wu Tian Lan Yingjie Zhang Xiaolan Guo Huanan Wang Mohammad Saleem Cheng Jiang Junxuan Lu Yibin Deng |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T08:23:31Z |
| format | Article |
| id | doaj.art-6db2a0442aa347f1b653dd07c6bb4ec7 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-17T08:23:31Z |
| publishDate | 2016-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6db2a0442aa347f1b653dd07c6bb4ec72022-12-21T21:56:50ZengElsevierEBioMedicine2352-39642016-05-017C506110.1016/j.ebiom.2016.03.022Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancerLei Wang0Ji Wang1Hua Xiong2Fengxia Wu3Tian Lan4Yingjie Zhang5Xiaolan Guo6Huanan Wang7Mohammad Saleem8Cheng Jiang9Junxuan Lu10Yibin Deng11Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USADepartment of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USADepartment of Pharmacology, Penn State College of Medicine, Hershey, PA, 17033, USALaboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN, 55912, USACurrently, 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.http://www.sciencedirect.com/science/article/pii/S2352396416301098Warburg effectAutophagyPTENTP53Hexokinase 2AMPKULK-1MCL-12-Deoxy-glucoseChloroquineAndrogen receptorCastration-resistant prostate cancerGenetically-engineered mouse model |
| spellingShingle | Lei Wang Ji Wang Hua Xiong Fengxia Wu Tian Lan Yingjie Zhang Xiaolan Guo Huanan Wang Mohammad Saleem Cheng Jiang Junxuan Lu Yibin Deng Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer EBioMedicine Warburg effect Autophagy PTEN TP53 Hexokinase 2 AMPK ULK-1 MCL-1 2-Deoxy-glucose Chloroquine Androgen receptor Castration-resistant prostate cancer Genetically-engineered mouse model |
| title | Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer |
| title_full | Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer |
| title_fullStr | Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer |
| title_full_unstemmed | Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer |
| title_short | Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer |
| title_sort | co targeting hexokinase 2 mediated warburg effect and ulk1 dependent autophagy suppresses tumor growth of pten and tp53 deficiency driven castration resistant prostate cancer |
| topic | Warburg effect Autophagy PTEN TP53 Hexokinase 2 AMPK ULK-1 MCL-1 2-Deoxy-glucose Chloroquine Androgen receptor Castration-resistant prostate cancer Genetically-engineered mouse model |
| url | http://www.sciencedirect.com/science/article/pii/S2352396416301098 |
| work_keys_str_mv | AT leiwang cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT jiwang cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT huaxiong cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT fengxiawu cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT tianlan cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT yingjiezhang cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT xiaolanguo cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT huananwang cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT mohammadsaleem cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT chengjiang cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT junxuanlu cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer AT yibindeng cotargetinghexokinase2mediatedwarburgeffectandulk1dependentautophagysuppressestumorgrowthofptenandtp53deficiencydrivencastrationresistantprostatecancer |