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

• Published in: Frontiers in oncology 2022-01, Vol.11, p.794959-794959
• Main Authors: Wang, Qian, Wei, Xin, Hu, Lanyan, Zhuang, Lingling, Zhang, Hong, Chen, Qi
• Format: Article
• Language: English
• Subjects: cisplatin resistance; Gli2; hedgehog signaling; MDR1; Oncology; ovarian cancer; proliferation
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2021.794959

Cisplatin (DDP) resistance remains a key challenge in improving the clinical outcome of patients with ovarian cancer (OC). overexpression can lead to DDP resistance in OC cells, but the specific underlying regulatory mechanism remains unclear. The membrane transporter encoding gene positively regulates chemotherapy resistance in various cancer types. We evaluated as a potential downstream target and the contribution of the axis in promoting DDP resistance in OC cells. To generate drug-resistant SKOV3/DDP cells, SKOV3 cells were grown for six months under continuous induction wherein the DDP concentration was steadily increased. 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 by 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 affected DDP resistance in OC . DDP-resistant SKOV3/DDP and A2780/DDP cells showed higher expression of and as compared with that in DDP-sensitive OC cells. knockdown in SKOV3/DDP cells significantly reduced 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 , treatment with gradient concentrations of verapamil, an MDR1 inhibitor, significantly inhibited expression. Our findings indicate that downregulation of expression may reverse OC cell resistance to DDP. Moreover, dual-luciferase reporter gene assays confirmed that is a direct downstream target of , with positively regulating expression. Finally, subcutaneous xenotransplantation in nude mice demonstrated that plays a key role in regulating OC drug resistance. We identified a mechanism by which Hedgehog- signaling regulates OC chemoresistance by modulating expression. Hence, and are potential biomarkers and therapeutic targets in patients with chemoresistant OC.