Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species.

He Zhang,Baoai Han,Yanfen Cui,Fei Zhang,Zhaosong Wang,Hui Liu,Xiaoyan Zuo,Ruifang Niu,Sixin Ren,Ran Tian,Xingxing Han,Jianfei Tian,Zhiyong Wang,Yuying Zhu

doi:10.3389/fcell.2021.719209

Abstract

ATP-binding cassette (ABC) transporter family are major contributors to the drug resistance establishment of breast cancer cells. Breast cancer resistant protein (BCRP), one of the ABC transporters, has long been recognized as a pump that effluxes the therapeutic drugs against the concentration gradient. However, recent studies suggest that the biological function of BCRP is not limited in its drug pump activity. Herein, the role of BCRP in the proliferation and survival of drug-resistant breast cancer cells was investigated. We found that BCRP is not the major drug pump to efflux epirubicin in the resistant cells that express multiple ABC transporters. Silencing of BCRP significantly impairs cell proliferation and induces apoptosis of the resistant cells in vitro and in vivo. RNA-sequencing and high-throughput proteomics suggest that BCRP is an inhibitory factor of oxidative phosphorylation (OXPHOS). Further research suggests that BCRP is localized in the mitochondria of the resistant cells. Knockdown of BCRP elevated the intracellular reactive oxygen species level and eventually promotes the cell to undergo apoptosis. This study demonstrated that BCRP exerts important onco-promoting functions in the drug-resistant breast cancer cells independent of its well-recognized drug efflux activity, which shed new light on understanding the complex functional role of ABC transporters in drug-resistant cells.

Highlights

Breast cancer is one of the major malignant tumors in women, accounting for 30% of all newly diagnosed cancers in women worldwide (Sung et al, 2021)
These results suggested that Breast cancer resistant protein (BCRP) was not the dominant drug pump that contributed to the exclusion of EPI in the two specific drug-resistant cell models that expressed multiple ATP-binding cassette (ABC) transporters
Several reports have pointed out that the dysregulation of ABC transporters is connected with aggressive phenotypes of cancers, e.g., invasion and metastasis, evasion of apoptosis, sustained proliferation, and the emergence of cancer stem cells (Begicevic and Falasca, 2017; Muriithi et al, 2020)

Summary

Introduction

Breast cancer is one of the major malignant tumors in women, accounting for 30% of all newly diagnosed cancers in women worldwide (Sung et al, 2021). Chemotherapy plays an important role in the management of breast cancer; cancer cells always develop drug-resistance ability, which greatly limits the outcome of chemotherapeutic treatment (Fletcher et al, 2016). The. BCRP Sustains Survival and Proliferation establishment of the drug resistance ability of cancer cells is a long-term multistage process that is accompanied by complex reprogramming. Cells always acquire a strong ability to export the chemotherapy drugs, thereby increasing the difficulty of their elimination by treatments (Holohan et al, 2013; Kathawala et al, 2015; Fletcher et al, 2016). Drug-resistant cells establish strong capabilities to survive, even in the fluctuated environment in which they are not favored (Bukowski et al, 2020). Understanding the molecular foundation that supports the enhanced survival phenotype of drug-resistant cells is needed

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