Curcumin Suppresses Cisplatin Resistance Development Partly Via Modulating Extracellular Vesicle-mediated Transfer of MEG3 and MiR-214 in Ovarian Cancer

Purpose: To investigate how curcumin alters the extracellular vesicles' (EVs) capability to ship drug resistance in ovarian cancer.

Methods: The EVs from cisplatin-resistant A2780cp cells with curcumin treatment (EVs-CU) or without curcumin treatment (EVs-N) were collected for lncRNA profiling. Curcumin's effect on MEG3 promoter methylation and MEG3 expression were studied by MSP and qRT-PCR, respectively. The regulative effect of MEG3 on miR-214 expression and the functional role of EVs mediated transfer of miR-214 in cisplatin resistance were further investigated.

Results: Curcumin weakened the EVs-N's capability to induce drug resistance and induced significant changes of lncRNAs in the EVs. MEG3 is one of the most upregulated lncRNAs. Curcumin led to demethylation in the promoter region of MEG3 and 5-AZA-dC treatment restored MEG3 expression in a dose dependent manner. There were at least two binding sites between MEG3 and miR-214. MEG3 restoration by curcumin significantly reduced miR-214 in cells and in EVs. Functionally, miR-214 inhibition weakened the EVs-N's capability to enhance chemoresistance, while miR-214 overexpression increased the capability of EVs-CU in inducing chemoresistance.

Conclusion: Curcumin can restore MEG3 levels via demethylation. MEG3 upregulation can decrease EVs mediated transfer of miR-214 in ovarian cancer cells, thereby reducing drug resistance.