Vielanin K enhances doxorubicin-induced apoptosis via activation of IRE1α- TRAF2 - JNK pathway and increases mitochondrial Ca2 + influx in MCF-7 and MCF-7/MDR cells

Background: Therapeutic failure and drug resistance are common and have important implications in the poor prognosis of advanced breast Cancer. It is necessary to acquire a natural product to overcome the resistance of Cancer and increase the sensitivity of drug-resistant cells to Anticancer agents.

Purpose: To demonstrate whether the compound Vielanin K (VK) has the potential to increase the sensitivity of MCF-7 and MCF-7/MDR cells to Anticancer agents.

Methods: Cell viability and proliferative capacity were determined by MTT, colony formation and EdU assays. Apoptosis and CA²⁺ accumulation were evaluated by flow cytometry. Then, proteins were detected by immunoblotting, and gene expression levels were explored by qRT-PCR.

Results: In MCF-7 and corresponding MDR cells, VK increased the fluorescence intensity of Rho123, but not CFDA. VK treatment did not affect the protein expression of P-gp, MRP1 or BCRP. VK treatment enhanced the DOX-induced apoptotic cascade, while VK combined with DOX increased JNK phosphorylation by activating the IRE1α-TRAF2 signaling pathway. In addition, CA²⁺ was released from the endoplasmic reticulum following combination treatment, thereby giving rise to mitochondrial Apoptosis. Silencing IRE1α and JNK with small interfering RNA (siRNA) efficiently attenuated combination treatment-induced Apoptosis. These effects caused mitochondrial depolarization and reduced viability in MCF-7 and corresponding MCF-7/MDR cells.

Conclusion: VK combined with DOX increases the Apoptosis of MCF-7 and corresponding MCF-7/MDR cells by activating ER stress and mitochondrial Apoptosis via IRE1α-TRAF2-JNK signaling.