抄録
Cisplatin is one of the most active drugs for the treatment of cancers. However, cisplatin-induced nephrotoxicity is the most common problem. Although the counteracting apoptotic and survival pathways are balanced as the injured cells either undergo apoptosis or proliferate, the switch molecule of this balance is unclear. This study investigated the expression of Phlda3 as a potential biomarker of renal tubular injury induced by cisplatin in vivo and in vitro, and its functional role in cisplatin-induced toxicity. Phlda3 transcript and protein levels were highly up-regulated in the kidney of mice after cisplatin treatment, which preceded increases in BUN or serum creatinine. Particularly, the level of Phlda3 transcript was substantially increased at an early time, and remained elevated. Treatment of NRK52E with cisplatin caused increases in Phlda3 mRNA and protein. Knockdown of Phlda3 reversed the decrease in cell viability by cisplatin. Cisplatin treatment elicited p53 accumulation via Akt/Mdm2 repression. Phlda3 deficiency attenuated a decrease in Akt phosphorylation by cisplatin, and prevented p53 accumulation. Hence, Phlda3, which leads to p53-mediated tubular cell death, may be an early and sensitive biomarker of cisplatin-induced kidney injury. To assess the effect of Phlda3 inhibition on the anti-cancer effect of cisplatin, we determined whether Phlda3 knockdown diminishes its anti-cancer effect. Cisplatin elicited SKOV-3 cell death, which was not reversed by Phlda3 knockdown, implying that the method to inhibit Phlda3 may be of use in decreasing kidney toxicity without losing the anti-cancer effect of cisplatin.
