Abstract
BackgroundAutophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H+ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation.MethodsAutophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription–PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues.ResultsAutophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3).ConclusionActivation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.
Highlights
Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress
Autophagy promoted hepatocellular carcinoma (HCC) cell glycolysis by upregulating Monocarboxylate transporter 1 (MCT1) We examined whether autophagy can promote HCC cell glycolysis
Western blotting showed that the β-catenin knockdown decreased MCT1 expression significantly (Fig. 5c), and decreased glucose consumption and lactate production rates (Fig. 5d–g). These findings indicate that autophagy upregulates MCT1 and induces HCC cell glycolysis by activating Wnt/β-catenin signaling
Summary
Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H+ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation. Studying the key molecular mechanism of HCC development is a high priority for discovering an effective treatment. HCC development is accompanied by cell energy metabolism that changes from oxidative phosphorylation to aerobic glycolysis, and which is termed the Warburg effect [2]. This metabolic pathway transformation ensures adequate energy supply to tumor cells, and provides sufficient materials for rapid proliferation. A gas chromatography–mass spectrometry study of the metabonomics of 31 HCC tissues and paracancerous tissues showed that HCC tissues had twice the metabolism rate for glucose, glycerol 3-phosphoric acid, malic acid, alanine, inositol, and linoleic acid compared to the paracancerous
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