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Background  Cisplatin (DDP) resistance remains a key challenge in improving the clinical outcome of patients with ovarian cancer (OC).  Gli2  overexpression can lead to DDP resistance in OC cells, but the specific underlying regulatory mechanism remains unclear. The membrane transporter encoding gene  MDR1  positively regulates chemotherapy resistance in various cancer types. We evaluated  MDR1  as a potential  Gli2  downstream target and the contribution of the  Gli2/MDR1  axis in promoting DDP resistance in OC cells.    Methods  To generate drug-resistant SKOV3/DDP cells, SKOV3 cells were grown for six months under continuous induction wherein the DDP concentration was steadily increased.  Gli2  expression in OC cells with varying DDP sensitivities was detected using western blot. Cell counting kit-8 assays were used to assess the DDP sensitivity of SKOV3, SKOV3/DDP, A2780, and A2780/DDP cells and reversal of DDP resistance in SKOV3/DDP and A2780/DDP cells. Cell proliferation was analyzed using 5-ethynyl-2′-deoxyuridine (EdU) incorporation assays. The transcriptional regulation of  MDR1  by  Gli2  was determined using luciferase reporter assays. Finally, xenograft OC tumors were generated in nude mice, which were then treated with intraperitoneal DDP or phosphate-buffered saline (PBS) injections to investigate if  Gli2  affected DDP resistance in OC  in vivo .    Results  DDP-resistant SKOV3/DDP and A2780/DDP cells showed higher expression of  Gli2  and  MDR1  as compared with that in DDP-sensitive OC cells.  Gli2  knockdown in SKOV3/DDP cells significantly reduced  MDR1  expression, whereas it increased DNA damage, thereby sensitizing OC cells to DDP. Similar results were obtained after targeting Gli2 expression with the Gli-antagonist 61 inhibitor (GANT61) in SKOV3/DDP and A2780/DDP cells. In cells stably overexpressing  Gli2 , treatment with gradient concentrations of verapamil, an MDR1 inhibitor, significantly inhibited  MDR1  expression. Our findings indicate that downregulation of  MDR1  expression may reverse OC cell resistance to DDP. Moreover, dual-luciferase reporter gene assays confirmed that  MDR1  is a direct downstream target of  Gli2 , with  Gli2  positively regulating  MDR1  expression. Finally, subcutaneous xenotransplantation in nude mice demonstrated that  Gli2  plays a key role in regulating OC drug resistance.    Conclusions  We identified a mechanism by which Hedgehog- Gli  signaling regulates OC chemoresistance by modulating  MDR1  expression. Hence,  Gli2  and  MDR1  are potential biomarkers and therapeutic targets in patients with chemoresistant OC.

Hedgehog−Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1