Frontiers in Pharmacology (May 2020)
Obg-Like ATPase 1 Enhances Chemoresistance of Breast Cancer via Activation of TGF-β/Smad Axis Cascades
Abstract
Understanding the molecular mechanism of drug resistance helps to identify an effective target for breast cancer therapy. In this study we investigated the regulatory role of Obg-like ATPase 1 which is involved in multiple uses of drug resistance against breast cancer. Paclitaxel resistant cell line (MCF-7-PTR) was developed by a continuous increasing paclitaxel concentration. MTT assay was used to validate either acquired resistant or OLA1 modified cell lines. qRT-PCR, western blotting, apoptosis, and cell cycle assays were executed to evaluate gene and protein expression in cell lines. A series of in vitro assays was performed in the cells with RNAi-mediated knockdown to expound the regulatory function of OLA1 in breast cancer. We demonstrated that OLA1 was highly correlated with either acquired or intrinsic resistance of breast cancer. Further study showed that escalated expression of OLA1 promoted the EMT process in tumor cells through TGF-β/Smad signaling cascades, resulting in the enhanced expression of anti-apoptosis-related proteins (cleaved caspase3, Bax, Bcl-2) and the strengthening depolymerization of microtubules in tumor cells. Our findings revealed that OLA1 enhanced the anti-apoptotic ability and elucidated a regulatory role of OLA1 in promoting chemotherapy resistance of breast cancer. Chemo-sensitivity of the disease can be thus enhanced significantly by knocked down OLA1, which led to the inactivation of the TGF-β/Smad signaling cascades, polymerized microtubules, and promoted cell apoptosis. Our data suggest that OLA1 may be developed as a potential target to improve chemotherapy of patients with breast cancer.
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