PGAM1 Modulates Paclitaxel-Resistance in Ovarian Cancer Cells Through Controlling Pyruvic Acid Production in Glycolysis

Background: Enhanced glycolysis occurs in most human cancer cells and is considered to be related to chemoresistance. However, detailed mechanisms remain vague.Methods: Using proteinomics, PGAM1 was identified to be related to paclitaxel resistance. The correlations between PGAM1 expression, overall survival and progression free survival were evaluated for ovarian cancer patients. We also detected differences in pyruvic acid production, lactic acid production and mitochondrial function between SKOV3 and SKOV3-TR30 and explored PGAM1 function by altering its expression in vitro, along with examining any correlated changes in paclitaxel resistance.Findings: PGAM1 was highly expressed in the paclitaxel resistant ovarian cancer cell line SKOV3-TR30, as compared to its parental cell line SKOV3. A high expression of PGAM1 was significantly correlated with a reduced overall survival and progression free survival in ovarian cancer patients. SKOV3-TR30 cells represent higher glycolytic activities and lower mitochondrial function than SKOV3 cells. Down-regulation of PGAM1 in SKOV3-TR30 cells resulted in decreased paclitaxel resistance, and up-regulation of PGAM1 in SKOV3 cells led to enhanced paclitaxel resistance. Analysis of the glycolytic flux revealed that PGAM1-mediated pyruvic acid or lactic acid production could control the capabilities of ovarian cancer cell resistance to paclitaxel in vitro.Interpretation: PGAM1 could act as a modulator linked to paclitaxel sensitivity in ovarian cancer cells. Blocking PGAM1 may provide a new approach to reverse paclitaxel resistance in ovarian cancer patients.Funding Statement: This work was supported by Medicine and Health Research Project of Zhejiang Province (No.2017211914), the grant from the Research Project in Health Commission of Zhejiang Province (No.2013KYA106).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The study was approved by the Research Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University.