HSF1/AMPK?2 mediated alteration of metabolic phenotypes confers increased oxaliplatin resistance in HCC cells.

ABSTRACT: Recent studies suggest that up-regulated HSF1 possesses metabolic phenotypes switch and chemoresistance in cancer cells. However, the mechanism in which these characteristics are still ambiguous. Our study aims to identify how HSF1 confers chemoresistance through regulating metabolic pathway in hepatocellular carcinoma (HCC). Oxaliplatin (OXA)-resistant HCC cells (HCC-OXR) in both of abundant glucose (AG; 25 mM) and low glucose (LG; 5.5 mM) conditions were constructed; then glucose consumption, lactate production, intracellular ATP level and oxygen consumption of parental and OXA-resistant cells were determined by using the associated detected kits. Moreover, HSF1 was knocked down to analyze its effects on metabolic phenotypes alteration and chemoresistance formation in HCC cells. Compared to cells in AG condition, HCC cells delayed to form chemoresistance to OXA in LG condition; and OXA-resistant cells underwent a metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS), which presented decreased glucose uptake and lactate production with increased levels of oxygen consumption and intercellular ATP; interestingly, this energy-producing pathway was blocked in HSF1-knockdown OXA-resistant cells, especially in LG condition. Analysis on previous data revealed that AMPK pathway was a critical regulator in the metabolism of OXA-resistance HCC cells. Furthermore, AMPK?2 was identified as an important factor regulated by HSF1 to achieve metabolic phenotype switch in OXA-resistance HCC cells. Consequently, these results suggest that combining restrictive glucose uptake and targeting HSF1/AMPK?2 is an attractive strategy to prevent chemoresistance to OXA in HCC patients.

SUBMITTER: Shen JH 

PROVIDER: S-EPMC6895450 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature