Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma
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(2020) 18:131
RESEARCH
Open Access
Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma Chuanzong Zhao1,2, Ben Wang1, Enyu Liu1 and Zongli Zhang1*
Abstract Background: Metabolic reprogramming, in which energetic metabolism changes from oxidative phosphorylation to glycolysis, is well-accepted as a hallmark of cancers including hepatocellular carcinoma (HCC). A growing body of evidence suggests the involvement of oncogenes and tumor suppressor genes in the control of metabolic reprogramming. In this study, we attempt to investigate whether loss of PTEN, a recognized tumor suppressor, drives metabolic reprogramming of HCC. Methods: Cancerous liver tissues were surgically resected from 128 HCC patients, with 43 adjacent noncancerous liver tissues as control. Aerobic glycolysis (Warburg effect) was reflected by measurements of glucose uptake and lactate production, mitochondrial membrane potential collapse was observed by JC-1 staining, glycolytic rate and mitochondrial respiration were evaluated by determining glycolytic proton efflux rate (glycoPER) and oxygen consumption rate (OCR) in cultured human HHCC cells. Results: Reciprocal expression of PTEN and PI3K was determined in cancer liver tissues. Overexpression of PTEN suppressed the Warburg effect, as evidenced by reductions in glucose uptake and lactate production, maintenance of mitochondrial function, and transformation of energetic metabolism from glycolysis to oxidative phosphorylation in cultured PTEN-negative HHCC cells. Importantly, 740 Y-P, a PI3K agonist that leads to activation of the PI3K pathway, partially abrogated the function of PTEN and reprogramed glucose metabolism in cultured HHCC cells. Conclusions: The discovery that loss of PTEN allows the tumor metabolic program has been a major advance in understanding the carcinogenesis of HCC. Keywords: Hepatocellular carcinoma, Metabolic reprogramming, Warburg effect, PTEN, PI3K pathway, Glucose uptake, Lactate production
Background Hepatocellular carcinoma (HCC) represents a malignant tumor predominantly arising in the setting of cirrhosis, causing an estimated one million deaths on a global scale in 2030 [1]. According to the Global Cancer Statistics 2018, the mortality rate of HCC is only second to lung cancer in males by gender stratification [2]. Most of * Correspondence: [email protected] 1 Department of General Surgery, Qilu Hospital of Shandong University, No. 107, Wenhua West Road, Lixia District, Jinan 250012, Shandong Province, P. R. China Full list of author information is available at the end of the article
HCC cases at their initial diagnosis have reached the advanced stage, which results in poor patient survival [3]. An enhanced understanding of the mechanism underlying HCC pathogenesis, recurrence and metastasis is required to achieve early diagnosis and to further develop more effective treatment modalities. Cancer cells preferentially consume glucose and glutamine to fuels uncontrolled cell proliferation and pr
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