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
2020
Zhang, Li-Na | Xia, Yuan-Zheng | Zhang, Chao | Zhang, Hao | Luo, Jian-Guang | Yang, Lei | Kong, Ling-Yi
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.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.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.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.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.
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