Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

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.

Capacitation promotes a shift in energy metabolism in murine sperm

“…The addition of the metabolic modulators used in the second set of EFAs allowed us to calculate several metabolic parameters ( Supplementary Table S1 ) that have more informative value than the raw normalized measurements. They also allowed for a more accurate comparison between the two incubation conditions ( Marinangeli et al, 2018 ; Zhao et al, 2020 ). Metabolic parameters were calculated for each well as the average value of the measurements taken for that well in condition A minus the average value of the measurements taken for that well in condition B (see Supplementary Table S1 for a description of the conditions and Supplementary Figure S2 for a graphical representation).…”

Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk

“…Similarly, Stiles et al reported that hepatic Pten deletion in mice induced an increased glycogen synthesis in the liver [ 104 ]. In vitro, PTEN deficiency in human HCC cell lines (HepG2 and Huh7) is further associated with an increased glucose consumption [ 105 ], whereas its overexpression decreased glucose uptake by the HHCC cells [ 106 ]. Taken together, these previous studies clearly indicate that PTEN knockdown or knockout in hepatocytes triggers an increased glucose utilization.…”

Capacitation promotes a shift in the energy metabolism in murine sperm

“…The addition of the metabolic modulators used in the second set of EFAs allowed us to calculate several metabolic parameters (Table S1) that have more informative value than the raw normalized measurements. They also allowed for a more accurate comparison between the two incubation conditions [74,75]. Metabolic parameters were calculated for each well as the average value of the measurements taken for that well in condition A minus the average value of the measurements taken for that well in condition B (see Table S1 for a description of the conditions and Fig.…”