Mitochondrial dynamics regulates migration and invasion of breast cancer cells.
Mitochondrial dynamics regulates migration and invasion of breast cancer cells.
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作者：
Zhao, J.;Zhang, J.;Yu, M.;Xie, Y.;Huang, Y.;Wolff, D. W.;Abel, P. W.;Tu, Y.
线粒体具有高度动态性，不断进行融合与分裂，这对于维持细胞的生理功能至关重要。尽管线粒体功能障碍与肿瘤发生有关，但线粒体动态变化在癌症主要致死原因——转移过程中的作用却鲜为人知。在本研究中，我们发现人类浸润性乳腺癌及淋巴结转移灶中线粒体分裂蛋白动力相关蛋白1（Drp1）的表达显著上调。与非转移性乳腺癌细胞相比，转移性乳腺癌细胞中的线粒体更为碎片化，这些细胞中总Drp1和活性Drp1水平更高，而线粒体融合蛋白1（Mfn1）水平更低。沉默Drp1或过表达Mfn1分别导致线粒体伸长或聚集，并显著抑制乳腺癌细胞的转移能力。相反，沉默Mfn蛋白会导致线粒体碎片化，并增强乳腺癌细胞的转移能力。有趣的是，这些对线粒体动态变化的调控改变了乳腺癌细胞中线粒体的亚细胞分布。例如，沉默Drp1或过表达Mfn1会抑制片状伪足的形成（癌症转移的关键步骤），并抑制趋化因子诱导的线粒体向片状伪足区域的募集。反之，沉默Mfn蛋白会导致更多的细胞铺展和片状伪足形成，使更多线粒体在片状伪足区域积累。更重要的是，用线粒体解偶联剂或ATP合成抑制剂处理可减少片状伪足的形成，降低乳腺癌细胞的迁移和侵袭能力，这表明线粒体在乳腺癌转移中具有重要功能。总之，我们的研究结果揭示了线粒体动态变化调控癌细胞迁移和侵袭的新作用及机制。因此，针对失调的Drp1依赖性线粒体分裂进行靶向干预，可能为抑制乳腺癌转移提供一种新策略。
Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found a marked upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1) expression in human invasive breast carcinoma and metastases to lymph nodes. Compared to non-metastatic breast cancer cells, mitochondria also were more fragmented in metastatic breast cancer cells that express higher levels of total and active Drp1 and less mitochondrial fusion protein 1 (Mfn1). Silencing Drp1 or overexpression of Mfn1 resulted in mitochondria elongation or clusters, respectively, and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silencing Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics altered the subcellular distribution of mitochondria in breast cancer cells. For example, silencing Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silencing Mfn proteins resulted in more cell spreading and lamellipodia formation, causing accumulation of more mitochondria in lamollipodia regions. More importantly, treatment with a mitochondrial uncoupling agent or ATP synthesis inhibitor reduced lamellipodia formation and decreased breast cancer cell migration and invasion, suggesting a functional importance of mitochondria in breast cancer metastasis. Together, our findings show a new role and mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting dysregulated Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing breast cancer metastasis.
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影响因子：
3.5
作者：
Biswas, S;Ray, M;Ray, S
通讯作者：
Ray, S
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
DOI：
10.1016/0005-2728(74)90175-3
发表时间：
1974-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
BERTINA, RM;STEENSTRA, JA;SLATER, EC
通讯作者：
SLATER, EC