BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism

Lifang Luo,Wenjing Sun,Daoquan Fang,Xiaohui Xu,Yihu Zheng,Weijian Zhu,Tan Hooi Min Grahn,Shuhan Li,Wenqi Zhang,Lei Jiang

doi:10.1038/s41419-021-03456-7

Abstract

Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.

Highlights

Cisplatin, a broad-spectrum anti-tumor chemotherapeutic agent, is used in clinical practice for the treatment of various types of tumors[1], including hepatocellular carcinoma (HCC) and cervical cancer
BCAT1 expression decreases cisplatin cytotoxicity in cancer cells The expression levels of BCAT1 were detected by qRT
To determine the functional role of BCAT1 with respect to cisplatin sensitivity, BCAT1 was overexpressed in the Human cervical cancer cell line (Hela) and Huh-7 cells, which express low levels of BCAT1 (Fig. 1C and S1B), using a lentiviral vector

Summary

Introduction

A broad-spectrum anti-tumor chemotherapeutic agent, is used in clinical practice for the treatment of various types of tumors[1], including hepatocellular carcinoma (HCC) and cervical cancer. Luo et al Cell Death and Disease (2021)12:169 involvement of BCAT1 in cisplatin cytotoxicity remain undefined. The activation of mTOR inhibits autophagy flux[17]. Autophagy is an important homeostasis program that is responsible for removing dysfunctional or damaged organelles in all living cells[18]. Various stimulations, such as starvation, growth factor withdrawal, hypoxia and genotoxic or oxidative stress, can induce autophagy[19,20]. Autophagy is considered a double-edged sword, because it has tumorpromoting and tumor-suppressing properties[18]. Autophagy is suggested to mediate a cancer cell’s resistance to chemotherapy and radiation treatment[21,22]. Various studies show that autophagy contributes to cisplatin chemoresistance, and inhibiting autophagy, perhaps, is a means for overcoming cisplatin resistance[23,24,25]

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Conclusion