Reduced expression of enolase-1 correlates with high intracellular glucose levels and increased senescence in cisplatin-resistant ovarian cancer cells

摘要

Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop a platinum-resistant disease with a poor overall prognosis. The molecular events leading to the cisplatin resistance of ovarian cancer cells are not fully understood. Here, we performed a proteomic analysis to identify protein candidates deregulated in a cisplatin-resistant ovarian cancer cell line (A2780CP20) in comparison to their sensitive counterpart (A2780). Forty-eight proteins were differentially abundant in A2780CP20, as compared with A2780, cells. Enolase-1 (ENO1) was significantly decreased in cisplatin-resistant ovarian cancer cells. Western blots and RT-PCR confirmed our findings. Ectopic ENO1 expression increased the sensitivity of ovarian cancer cells to cisplatin treatment. In contrast, small-interfering (siRNA)-based ENO1 silencing in A2780 cells reduced the sensitivity of these cells to cisplatin treatment. Whereas glucose consumption was lower, intracellular levels were higher in cisplatin-resistant ovarian cancer cells as compared with their cisplatin-sensitive counterparts. Senescence-associated β-galactosidase (β-Gal) levels were higher in cisplatin-resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. β-Gal levels were decreased in ENO1 overexpressed clones. Protein levels of the cell cycle regulators and senescence markers p21 and p53 showed opposite expression patterns in cisplatin-resistant compared with cisplatin sensitive cells. Our studies suggest that decreased expression of ENO1 promotes glucose accumulation, induces senescence, and leads to cisplatin resistance of ovarian cancer cells.