Inhibition of GSK-3β activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling.

Abstract

Glycogen synthase kinase-3 beta (GSK-3β) 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-3β in cancer metabolic process may facilitate the development of effective therapeutic approach for HCC. In this study, we showed that inhibition of GSK-3β led to diminished viability, metastasis and tumorigenicity in HCC cells. Suppression of GSK-3β 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 GSK3β inhibition demonstrated that GSK-3β was involved in glycolysis process of HCC. Mechanistically, the metabolic change and anti-cancer effect by GSK-3β 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-3β may become a promising therapeutic target for HCC.