CDCP1/线粒体Src轴增强电子传递链功能以促进三阴性乳腺癌转移。

CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer.

作者信息

Woytash Jordan A, Lefebvre Austin E Y T, Zhang Ziang, Xu Binzhi, Harchenko Stephanie A, Le Hoa T, McColloch Andrew R, Shi Xiaoyu, Digman Michelle A, Razorenova Olga V

机构信息

Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.

Department of Biomedical Engineering, University of California, Irvine, CA, USA.

出版信息

Br J Cancer. 2025 Sep 4. doi: 10.1038/s41416-025-03163-6.

DOI:10.1038/s41416-025-03163-6

PMID:40908298

Abstract

BACKGROUND

Triple-negative type of breast cancer (TNBC) has limited therapeutic options and frequently metastasizes, leading to low survival rates. Oxidative phosphorylation (OXPHOS) is a driver of TNBC metastasis, but the signaling underlying this metabolic change is poorly understood.

METHODS

We performed metabolic assays and assessed migratory and metastatic potential in cells with manipulated CDCP1/mitochondrial Src signaling.

RESULTS

We show that the pro-metastatic cell surface protein CUB-domain containing protein 1 (CDCP1) activates Src kinase localized in mitochondria, which potently induces OXPHOS and TNBC migration. Genetic targeting of either CDCP1 or mitochondrial Src, as well as pharmacological inhibition of Src reduce OXPHOS in vitro. We further show that mitochondrial Src increases OXPHOS by stimulating Complex I activity in the electron transport chain. Importantly, rescuing Complex I activity in cells devoid of CDCP1/mitochondrial Src signaling restores both OXPHOS and migration. We also provide evidence that NAD pool generated by Complex I is contributing to the observed migratory phenotype. Lastly, we determined that inhibiting mitochondrial Src reduces metastasis in TNBC cells.

CONCLUSIONS

Both CDCP1 and mitochondrial Src represent potential therapeutic targets to inhibit OXPHOS-mediated TNBC metastasis.

摘要

背景

三阴性乳腺癌（TNBC）的治疗选择有限，且常发生转移，导致生存率较低。氧化磷酸化（OXPHOS）是TNBC转移的驱动因素，但这种代谢变化背后的信号传导机制尚不清楚。

方法

我们进行了代谢分析，并评估了操纵CDCP1/线粒体Src信号的细胞的迁移和转移潜能。

结果

我们发现促转移细胞表面蛋白含CUB结构域蛋白1（CDCP1）激活定位于线粒体的Src激酶，从而有力地诱导OXPHOS和TNBC迁移。对CDCP1或线粒体Src进行基因靶向，以及对Src进行药理学抑制，均可在体外降低OXPHOS。我们进一步表明，线粒体Src通过刺激电子传递链中的复合体I活性来增加OXPHOS。重要的是，在缺乏CDCP1/线粒体Src信号的细胞中挽救复合体I活性可恢复OXPHOS和迁移能力。我们还提供证据表明，复合体I产生的NAD池促成了观察到的迁移表型。最后，我们确定抑制线粒体Src可减少TNBC细胞中的转移。