Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells

作者：Ling Huang, Guanjun Li, Ying Zhang, Ruishen Zhuge, Shijie Qin, Jinjun Qian, Ruixing Chen, Yin‐Kwan Wong, Huan Tang, Peili Wang, Wei Xiao, Jigang Wang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.10.021 · 被引用次数：24 · 研究领域：Cancer, Hypoxia, and Metabolism、Amino Acid Enzymes and Metabolism、Microtubule and mitosis dynamics

INTRODUCTION: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with the worst prognosis. Exploring novel carcinogenic factors and therapeutic drugs for TNBC remains a focus to improve prognosis. Branched-chain amino acid transaminase 1 (BCAT1), a crucial enzyme in branched-chain amino acid (BCAA) metabolism, has been linked to various tumor developments, but its carcinogenic function and mechanism in TNBC remain unclear. Eupalinolide B (EB) is a naturally-derived small-molecule with anti-tumor activity, but its role in TNBC remains unknown. OBJECTIVES: By exploring the targets and pharmacological mechanisms of EB in inhibiting TNBC, this study aimed to discover novel therapeutic targets and potential inhibitors for TNBC, and elucidate novel pathogenic mechanisms of TNBC. METHODS: The inhibitory effect of EB on TNBC was investigated using mouse models and cellular phenotypic experiments. Activity-based protein profiling (ABPP) technology, pull down-WB, CETSA-WB and MST were utilized to discover and validate the targets of EB. The oncogenic role of BCAT1 was determined through clinical data analysis and biochemical experiments. To elucidate the mechanism by which EB inhibited TNBC, many methods, including but not limited to HPLC and proteomic sequencing were used. RESULTS: We found that EB significantly inhibited TNBC progression. We identified BCAT1 as the direct target of EB and confirmed that BCAT1 was critical for TNBC development. EB inhi...