PMID- 31404613 OWN - NLM STAT- MEDLINE DCOM- 20200521 LR - 20211204 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 463 DP - 2019 Oct 28 TI - Inhibition of GSK-3beta activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling. PG - 11-26 LID - S0304-3835(19)30426-4 [pii] LID - 10.1016/j.canlet.2019.08.003 [doi] AB - Glycogen synthase kinase-3 beta (GSK-3beta) has been shown to play a critical role in the development of many cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. Deregulating cellular energetics is a signature hallmark of cancer, therefore modulating cancer metabolism has become an attractive anti-cancer approach in recent years. As a key enzyme in glucose metabolism, understanding the role of GSK-3beta in cancer metabolic process may facilitate the development of effective therapeutic approach for HCC. In this study, we showed that inhibition of GSK-3beta led to diminished viability, metastasis and tumorigenicity in HCC cells. Suppression of GSK-3beta activity also reduced glucose consumption, lactate production and adenosine triphosphate (ATP) levels in HCC cells. The decreased extracellular acidification rate (ECAR) and down-regulated key enzymes on the glycolysis pathway by GSK3beta inhibition demonstrated that GSK-3beta was involved in glycolysis process of HCC. Mechanistically, the metabolic change and anti-cancer effect by GSK-3beta inhibition was achieved mainly through activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, which negatively affected glycolysis and cell proliferation. The results from primary HCC cells and from in vivo nude mice model confirmed our observations. Our study results indicated that GSK-3beta may become a promising therapeutic target for HCC. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Fang, Guoxu AU - Fang G AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, 200438, Shanghai, China; Graduate School of Fujian Medical University, 350108, Fuzhou, Fujian Province, China; Mengchao Hepatobiliary Hospital, Fujian Medical University, 350025, Fuzhou, Fujian Province, China. FAU - Zhang, Peilin AU - Zhang P AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, 200438, Shanghai, China; National Center for Liver Cancer, 201805, Shanghai, China. Electronic address: peilinzhang8899@163.com. FAU - Liu, Jingfeng AU - Liu J AD - Mengchao Hepatobiliary Hospital, Fujian Medical University, 350025, Fuzhou, Fujian Province, China. FAU - Zhang, Xu AU - Zhang X AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, 200438, Shanghai, China; National Center for Liver Cancer, 201805, Shanghai, China. FAU - Zhu, Xiangjie AU - Zhu X AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, 200438, Shanghai, China; National Center for Liver Cancer, 201805, Shanghai, China. FAU - Li, Rong AU - Li R AD - Department of Pathology, Eastern Hepatobiliary Surgery Hospital, 200438, Shanghai, China. FAU - Wang, Hongyang AU - Wang H AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, 200438, Shanghai, China; National Center for Liver Cancer, 201805, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, 200032, Shanghai, China. Electronic address: hywangk@vip.sina.com. LA - eng PT - Journal Article DEP - 20190809 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (3-(9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro(1,4)diazepino(6,7,1-hi)indol-7-yl)-4-imidazo(1,2-a)pyridin-3-yl-1H-pyrrole-2,5-dione) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Heterocyclic Compounds, 3-Ring) RN - 0 (Maleimides) RN - 33X04XA5AT (Lactic Acid) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - IY9XDZ35W2 (Glucose) RN - P0EP9VFC4R (lucatumumab) SB - IM MH - AMP-Activated Protein Kinases/*physiology MH - Adenosine Triphosphate/metabolism MH - Antibodies, Monoclonal, Humanized/pharmacology MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Cells, Cultured MH - Glucose/metabolism MH - Glycogen Synthase Kinase 3 beta/*antagonists & inhibitors/metabolism/*physiology MH - Glycolysis/drug effects/*physiology MH - Heterocyclic Compounds, 3-Ring/pharmacology MH - Humans MH - Lactic Acid/metabolism MH - Liver Neoplasms/*metabolism MH - Maleimides/pharmacology MH - Neoplasm Metastasis MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*physiology OTO - NOTNLM OT - AMPK/mTOR signaling OT - GSK-3beta OT - Glycolysis EDAT- 2019/08/14 06:00 MHDA- 2020/05/22 06:00 CRDT- 2019/08/13 06:00 PHST- 2019/04/29 00:00 [received] PHST- 2019/08/06 00:00 [revised] PHST- 2019/08/07 00:00 [accepted] PHST- 2019/08/14 06:00 [pubmed] PHST- 2020/05/22 06:00 [medline] PHST- 2019/08/13 06:00 [entrez] AID - S0304-3835(19)30426-4 [pii] AID - 10.1016/j.canlet.2019.08.003 [doi] PST - ppublish SO - Cancer Lett. 2019 Oct 28;463:11-26. doi: 10.1016/j.canlet.2019.08.003. Epub 2019 Aug 9.