title: Blockage of glutaminolysis enhances the sensitivity of ovarian cancer cells to PI3K/mTOR inhibition involvement of STAT3 signaling.
abstract: The PI3K/Akt/mTOR axis in ovarian cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for ovarian cancer. However, ovarian cancer cells are resistant to PP242, a dual inhibitor of mTORC1 and mTORC2. Interestingly, blockage of GLS1 with a selective inhibitor, CB839, or siRNA dramatically sensitized the PP242-induced cell death, as evident from increased PARP cleavage. The anti-cancer activity of CB-839 and PP242 was abrogated by the addition of the TCA cycle product α-ketoglutarate, indicating the critical function of GLS1 in ovarian cancer cell survival. Finally, glutaminolysis inhibition activated apoptosis and synergistically sensitized ovarian cancer cells to priming with the mTOR inhibitor PP242. GLS1 inhibition significantly reduced phosphorylated STAT3 expression in ovarian cancer cells. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy to overcome resistance to PI3K/Akt/mTOR inhibition.
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.|Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan City, 442000, Hubei Province, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan City, 442000, Hubei Province, People's Republic of China.
authors.forename: Zhengqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Ensong
authors.initials: E
authors.lastname: Guo
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Wanying
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, Hubei, 430030, People's Republic of China. tjwcy66@qq.com.
authors.forename: Changyu
authors.initials: C
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D005972:Glutaminase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; C000593334:CB-839; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013830:Thiadiazoles; D005973:Glutamine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C579480:GLS protein, human; D005972:Glutaminase; C572919:PP242
keywords: Drug resistance; GLS1; Glutaminase1; Metabolic reprogramming; Ovarian cancer