Journal
CANCER LETTERS
Volume 463, Issue -, Pages 11-26Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.08.003
Keywords
GSK-3 beta; Glycolysis; AMPK/mTOR signaling
Categories
Funding
- National Natural Science Foundation of China [81472772]
- Natural Science Foundation of Shanghai [14ZR1408900]
- Major National Science and Technology Projects [2018ZX10302207]
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Glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta in cancer metabolic process may facilitate the development of effective therapeutic approach for HCC. In this study, we showed that inhibition of GSK-3 beta led to diminished viability, metastasis and tumorigenicity in HCC cells. Suppression of GSK-3 beta 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 GSK3 beta inhibition demonstrated that GSK-3 beta was involved in glycolysis process of HCC. Mechanistically, the metabolic change and anti-cancer effect by GSK-3 beta 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-3 beta may become a promising therapeutic target for HCC.
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