Xue Qiqi, Wang Wenxi, Liu Jie, Wang Dachi, Zhang Tianyu, Shen Tingting, Liu Xiangsheng, Wang Xiaojia, Shao Xiying, Zhou Wei, Fang Xiaohong
Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
J Transl Med. 2025 Mar 25;23(1):372. doi: 10.1186/s12967-024-05946-6.
Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.
Immunohistochemistry and sequencing data reanalysis were used to investigate LRPPRC expression in TNBC. In vitro and in vivo assays were applied to investigate the roles of LRPPRC in TNBC progression. RT-qPCR, immunoblotting, and Seahorse XF assay were used to examine LRPPRC's functions in the expression of OXPHOS subunits and energy metabolism. In vitro and in vivo functional assays were used to test the therapeutic effect of gossypol acetate (GAA), a traditional gynecological drug, on LRPPRC suppression and OXPOHS inhibition.
LRPPRC was specifically overexpressed in TNBC. LRPPRC knockdown suppressed the proliferation, metastasis, and tumor formation of TNBC cells. LRPPRC enhanced OXPHOS metabolism by increasing the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA inhibited OXPHOS metabolism by directly binding LRPPRC, causing LRPPRC degradation, and downregulating the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA administration suppressed TNBC cell proliferation, metastasis in vitro, and tumor formation in vivo.
This work demonstrated a new regulatory pathway of TNBC to promote the expression of mitochondrial genes by upregulating the nuclear gene LRPPRC, resulting in increased OXPHOS. We also suggested a promising therapeutic target LRPPRC for TNBC, and its inhibitor, the traditional gynecological medicine GAA, presented significant antitumor activity.
三阴性乳腺癌（TNBC）是一种高度恶性的肿瘤，需要有效的治疗靶点和药物。氧化磷酸化（OXPHOS）是TNBC的一种代谢弱点，但导致OXPHOS增强的分子机制仍不清楚。目前针对OXPHOS电子传递功能的策略无法区分肿瘤细胞和正常细胞。研究OXPHOS调控的机制并为TNBC开发相应的治疗策略具有重要意义。
采用免疫组织化学和测序数据再分析来研究TNBC中LRPPRC的表达。应用体外和体内实验来研究LRPPRC在TNBC进展中的作用。使用RT-qPCR、免疫印迹和海马XF分析来检测LRPPRC在OXPHOS亚基表达和能量代谢中的功能。使用体外和体内功能实验来测试传统妇科药物醋酸棉酚（GAA）对LRPPRC抑制和OXPOHS抑制的治疗效果。
LRPPRC在TNBC中特异性过表达。敲低LRPPRC可抑制TNBC细胞的增殖、转移和肿瘤形成。LRPPRC通过增加线粒体基因组编码的OXPHOS复合体亚基的表达来增强OXPHOS代谢。GAA通过直接结合LRPPRC、导致LRPPRC降解以及下调线粒体基因组编码的OXPHOS复合体亚基的表达来抑制OXPHOS代谢。给予GAA可抑制TNBC细胞的增殖、体外转移和体内肿瘤形成。
这项工作证明了TNBC通过上调核基因LRPPRC来促进线粒体基因表达从而导致OXPHOS增加的新调控途径。我们还提出了一个有前景的TNBC治疗靶点LRPPRC，其抑制剂传统妇科药物GAA具有显著的抗肿瘤活性。
