Mitochondrial dynamics regulates migration and invasion of breast cancer cells

J. Zhao, J. Zhang, M. Yu, Y. Xie, Y. Huang, D. W. Wolff, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticle

240 Citations (Scopus)

Abstract

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 with 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 lamellipodia regions. More importantly, treatment with a mitochondrial uncoupling agent or adenosine triphosphate 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.

Original languageEnglish
Pages (from-to)4814-4824
Number of pages11
JournalOncogene
Volume32
Issue number40
DOIs
StatePublished - Oct 3 2013

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Mitochondrial Dynamics
Dynamins
Mitochondria
Breast Neoplasms
Pseudopodia
Mitochondrial Proteins
Neoplasm Metastasis
Proteins
Cell Movement
Uncoupling Agents
Neoplasms
Chemotactic Factors
Cause of Death
Carcinogenesis
Up-Regulation
Adenosine Triphosphate
Lymph Nodes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Zhao, J., Zhang, J., Yu, M., Xie, Y., Huang, Y., Wolff, D. W., ... Tu, Y. (2013). Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene, 32(40), 4814-4824. https://doi.org/10.1038/onc.2012.494

Mitochondrial dynamics regulates migration and invasion of breast cancer cells. / Zhao, J.; Zhang, J.; Yu, M.; Xie, Y.; Huang, Y.; Wolff, D. W.; Abel, Peter W.; Tu, Yaping.

In: Oncogene, Vol. 32, No. 40, 03.10.2013, p. 4814-4824.

Research output: Contribution to journalArticle

Zhao, J, Zhang, J, Yu, M, Xie, Y, Huang, Y, Wolff, DW, Abel, PW & Tu, Y 2013, 'Mitochondrial dynamics regulates migration and invasion of breast cancer cells', Oncogene, vol. 32, no. 40, pp. 4814-4824. https://doi.org/10.1038/onc.2012.494
Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013 Oct 3;32(40):4814-4824. https://doi.org/10.1038/onc.2012.494
Zhao, J. ; Zhang, J. ; Yu, M. ; Xie, Y. ; Huang, Y. ; Wolff, D. W. ; Abel, Peter W. ; Tu, Yaping. / Mitochondrial dynamics regulates migration and invasion of breast cancer cells. In: Oncogene. 2013 ; Vol. 32, No. 40. pp. 4814-4824.
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