Platycodin D-mediated METTL16 downregulation promotes docetaxel treatment of prostate cancer by regulating ferroptosis.

BACKGROUND: The development of chemotherapy resistance critically constrains the therapeutic efficacy of docetaxel (DTX) in prostate cancer (PCa). Platycodin D (PD) is isolated from the plant Platycodon grandiflorus, and has been found to possess anti-tumor effect. However, whether PD can enhance the therapeutic effect of DTX on PCa and its related mechanisms have not yet been reported. METHODS: The effects of PD on PCa cell proliferation, apoptosis, and ferroptosis were examined in vitro. The impact of PD on tumorigenesis was assessed in vivo by utilizing a PCa cell xenograft mouse model. PCR array was used to determine the key gene regulated by PD. Transcriptome sequencing and MeRIP-PCR were implemented to explore the molecular mechanism of METTL16 in ferroptosis. RESULTS: We found that PD suppressed cell proliferation and induced cell apoptosis and ferroptosis in PCa cells. In addition, PD enhanced the therapeutic effect of DTX through triggering ferroptosis. PCR array results indicated that METTL16 was a crucial molecule in the regulation of PCa cell ferroptosis by PD, and PD significantly decreased METTL16 expression in PCa cells. Overexpression of METTL16 repressed PD-treated PCa cell ferroptosis. Mechanistically, METTL16 promoted the expression of NUPR1, and overexpression of METTL16 increased the m6A modification level of NUPR1. CONCLUSIONS: PD promotes PCa cell ferroptosis to enhance the therapeutic effect of DTX in PCa via the METTL16/m6A/NUPR1 axis. Our findings offer a novel strategy for improving the therapeutic efficacy of DTX in PCa.