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.
Highlights
Breast cancer is one of the leading fatal cancers among women worldwide
Epithelial-to-mesenchymal transition (EMT), which is associated with the acquisition of stem cell properties, metastasis, and resistance to therapy (Mani et al, 2008; Pastushenko et al, 2018), is a process in which the characteristics of epithelial cells change to the mesenchymal phenotype
We found that Obg-like ATPase 1 (OLA1) has a ubiquitous expression in the brain, thyroid, and 25 other tissues from the body map (Supplementary Figure 1A), and is highly expressed in breast cancer, pancreatic cancer, colorectal cancer, and other cancer tissues (Supplementary Figure 1B)
Summary
Breast cancer is one of the leading fatal cancers among women worldwide. According to statistics, there were an estimated 2.1 million breast cancer patients globally in 2018, and one out of every four female cancer patients is a breast cancer patient (Bray et al, 2018). Epithelial-to-mesenchymal transition (EMT), which is associated with the acquisition of stem cell properties, metastasis, and resistance to therapy (Mani et al, 2008; Pastushenko et al, 2018), is a process in which the characteristics of epithelial cells change to the mesenchymal phenotype. Exposure of tumor cells to TGF-b and TNF-a induces the EMT process and generates cells with a cancer stem cell-like phenotype, which is shown by the increased self-renewal capacity resulting in greatly improved tumorigenicity, and enhanced resistance to oxaliplatin, etoposide, and paclitaxel (Asiedu et al, 2011).TGF-b signaling possesses both Smad and non-Smad pathways, and crosstalk with numerous signal transduction pathways to advance EMT processes at multiple levels, including PI3K-AKT-mTOR, Wnt, Notch, and ERK, p38, and JUN N-terminal kinase (JNK) MAPK pathways (Xu et al, 2009; Lamouille et al, 2014). When TGF-b neutralizing antibodies were used to block the activity of TGF-b in tumor cells, breast cancer cells resumed sensitivity to the drug (Ohmori et al, 1998)
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