Zoledronic Acid-induced Cytotoxicity Through Endoplasmic Reticulum Stress Triggered REDD1-mTOR Pathway in Breast Cancer Cells

Background: Zoledronic acid (ZOL) used for the prevention/treatment of osteopathic complications has been reported to have antitumor effects in breast cancer treatment. However, little is known about the exact molecular mechanisms for antitumor actions of ZOL. In this study, two breast cancer cell lines were used to investigate the antitumor efficacy of ZOL and the underlying molecular mechanisms. Results: The growth of two breast cancer cell lines was markedly decreased following treatment with ZOL. Compared with MCF-7 cells, MDA-MB-231 cells were more sensitive to ZOL treatment. Western blot analysis showed that the inhibitory effect of zoledronic acid on growth was related to the extent of inhibition of phosphorylated-protein kinase B (p-AKT), and phosphorylated-mammalian target of rapamycin (p-mTOR). Moreover, the expression of the stress-responsive protein regulated in development and DNA damage response 1 (REDD1), an inhibitor of mTOR, was induced markedly to various degrees in different breast cancer cell lines after ZOL treatment. Interestingly, by examining the upstream signaling pathway of REDD1, we found that ZOL can induce endoplasmic reticulum stress responses through activating the protein kinase R (PKR)-related ER kinase-eukaryotic initiation factor 2 alpha-CCAAT/enhancer binding protein homologous protein (PERK-eIF2 alpha-CHOP) pathway. Conclusion: Taken together, these results indicated that ZOL-induced cell death was caused by endoplasmic reticulum stress activating PERK-eIF2 alpha-CHOP pathway to induce REDDI expression and inhibit the mTOR pathway.