Adrenomedullin induces cisplatin chemoresistance in ovarian cancer through reprogramming of glucose metabolism.

Abstract

The metabolic network of cancer cells has been reprogrammed - relying more on aerobic glycolysis to gain energy, which is an important reason for drug resistance. Expression of adrenomedullin (ADM) in ovarian cancer tissues is related to resistance to platinum-based drugs. In view of this, we intended to investigate the correlation between ADM and glucose metabolism reprogramming of tumor cells to clarify the possible mechanism of ADM-induced ovarian cancer cisplatin resistance through glucose metabolism reprogramming. Epithelial ovarian cancer (EOC) cell viability and apoptosis were determined. Different gene expression and protein levels were detected by real-time revere transcription polymerase chain reaction and western blotting. Oxygen consumption rate (OCR) and extracellular acidification rates (ECARs) were measured. ADM expression was upregulated in cisplatin-resistant EOC cells. ADM attenuated cisplatin-inhibited cell survival and cisplatin-induced apoptosis in sensitive EOC cells; knockdown of ADM enhanced cisplatin chemosensitivity of cisplatin-resistant EOC cells. ADM enhanced glycolysis in cisplatin-sensitive EOC cells; knockdown of ADM significantly inhibited glycolysis in cisplatin-resistant EOC cells. ADM significantly upregulated pyruvate kinase isozyme type M2 (PKM2) protein level, the key enzyme during glycolysis; PKM2 inhibitor significantly abolished the ADM-improved cell survival and ADM-inhibited apoptosis. ADM promoted proliferation and inhibited apoptosis of ovarian cancer cells through reprogramming of glucose metabolism, so as to promote cisplatin resistance. The study is expected to identify multidrug resistance markers of ovarian cancer and provide a target for the prevention and treatment of ovarian cancer, which is important for clinical translational research.