增强的线粒体裂变可抑制三阴性乳腺癌的信号转导和转移。
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer.
机构信息
Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
Department of Biomedical Engineering, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
出版信息
Breast Cancer Res. 2020 Jun 5;22(1):60. doi: 10.1186/s13058-020-01301-x.
BACKGROUND
Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC).
METHODS
We enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer.
RESULTS
Enforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer.
CONCLUSIONS
In TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.
背景
线粒体动力学是恶性转化、癌症进展和治疗反应的基础。目前的研究对线粒体分裂和融合在肿瘤进展中的功能提出了相互矛盾的证据。在这里，我们研究了线粒体分裂和融合状态如何调节三阴性乳腺癌 (TNBC) 中癌症进展和转移的潜在过程。
方法
我们通过化学或遗传方法强制改变线粒体分裂和融合状态，并测量 TNBC 细胞在 2D 和 3D 体外模型中的迁移和侵袭。我们还利用激酶易位报告器 (KTR) 来识别单个细胞中线粒体状态对信号级联的影响，PI3K/Akt/mTOR 和 Ras/Raf/MEK/ERK，这些在 TNBC 中通常被激活。此外，我们确定了分裂和融合状态对乳腺癌小鼠模型中的转移、骨破坏和信号的影响。
结果
通过化学或遗传方法强制线粒体分裂抑制了 TNBC 的迁移、侵袭和转移。具有主要分裂线粒体的乳腺癌细胞在体外和乳腺癌小鼠模型中均表现出 Akt 和 ERK 激活减少。用 Leflunomide（一种有效的线粒体融合蛋白激活剂）治疗可克服分裂对迁移、信号和转移的抑制作用。对乳腺癌的现有数据集进行挖掘表明，与线粒体分裂相关的基因表达增加与人类乳腺癌患者的生存改善相关。
结论
在 TNBC 中，线粒体分裂抑制与癌症进展和转移相关的细胞过程和信号通路。这些数据表明，促进线粒体分裂的治疗方法可能有益于患有乳腺癌的患者。
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