Background: Paclitaxel, as an anti-microtubule drug, has been recommended to be the first-line chemotherapy agent for ovarian cancer for about two decades. However, most patients with advanced stage relapse within two years and ultimately die of relapsed cancer displaying increased chemoresistance. The mechanisms underlying paclitaxel resistance remain ncompletely understood.
Methods: The paclitaxel-resistant ovarian cancer cell line SKOV3-TR30 and its parental cell line SKOV3 were analyzed by proteinomics. The glycolytic enzyme PGAM1-modulated glycolytic flux including pyruvic acid production and lactic acid production, and mitochondrial function was investigated using the assays kit. The correlations between PGAM1 expression, overall survival and progression free survival were evaluated for ovarian cancer patients. To elucidate the underlying mechanisms involved in paclitaxel resistance, PGAM1 gene knockout, gene overexpression and/or manipulation of glycolytic products were employed, followed by Western blot, immunostaining, and cell viability assay.
Results: 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 ignificantly correlated with a reduced overall survival and progression free survival in ovarian cancer patients. Under paclitaxel exposure, SKOV3 cells showed a stronger mitochondrial function than SKOV3-TR30 cells, suggesting that under the stress, SKOV3-TR30 cells had responded with enhanced glycolysis rather than undergoing oxidative phosphorylation. Down-regulation of PGAM1 in SKOV3 TR30 cells resulted in decreased paclitaxel resistance. Up-regulation of PGAM1 in SKOV3 cells led to enhanced paclitaxel resistance. Analysis of the lycolytic flux revealed that PGAM1-mediated pyruvic acid or lactic acid production could control the capabilities of ovarian cancer cell resistance to paclitaxel.
Conclusions: Our study demonstrated that 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.