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Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity

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Abstract

Mitochondrial dysfunction of cancer cells includes increased aerobic glycolysis, elevated levels of ROS, decreased apoptosis, and resistance to chemotherapeutic agents. We hypothesized that the introduction of normal mitochondria into cancer cells might restore mitochondrial function and inhibit cancer cell growth, and reverse chemoresistance. First, in the present study, we tested if mitochondria of immortalized, untransformed mammary epithelial MCF-12A cells could enter into human cancer cell lines. Second, if introducing normal mitochondria into cancer cells would inhibit proliferation. And third, would the addition of normal mitochondria increase the sensitivity of human breast cancer MCF-7 cells to chemotherapy. We found that JC-1-stained mitochondria of immortalized, untransformed mammary epithelial MCF-12A cells can enter into the cancer cell lines MCF-7, MDA-MB-231, and NCI/ADR-Res, but cannot enter immortalized, untransformed MCF-12A cells. The normal mitochondria from immortalized, untransformed MCF-12A cells suppressed the proliferation of MCF-7 and NCI/ADR-Res cells in a dose-dependent pattern, but did not affect the proliferation of immortalized, untransformed MCF-12A cells. The normal mitochondria from immortalized, untransformed MCF-12A cells increased the sensitivity of human breast cancer MCF-7 cells to doxorubicin, Abraxane, and carboplatin. In conclusion, the introduction of normal mammary mitochondria into human breast cancer cells inhibits cancer cell proliferation and increases the sensitivity of the MCF-7 human breast cancer cell line to doxorubicin, Abraxane, and carboplatin. These results support the role of mitochondrial dysfunction in cancer and suggest the possible use of targeted mitochondria for cancer therapeutics.

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Abbreviations

ROS:

Reactive oxygen species

MtDNA:

Mitochondrial DNA

SDH:

Succinate dehydrogenase

HIF:

Hypoxia-inducible factor

PHD:

Prolyl hydroxylase

VEGF:

Vascular endothelial growth factor

ATP:

Adenosine triphosphate

BAD:

Propaptotic ligand of Bcl-2 protein

BAX:

Multidomain proapoptotic Bcl-2 protein

PGC-1α:

Proliferator-activated receptor-γ coactivator

PPAR-γ:

Peroxisome proliferator-activated receptor

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Acknowledgments

We also want to thank Lisa Allen for her assistance in preparing this manuscript and illustrations. Without her help the task would have been almost impossible.

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Correspondence to R. L. Elliott.

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Elliott, R.L., Jiang, X.P. & Head, J.F. Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res Treat 136, 347–354 (2012). https://doi.org/10.1007/s10549-012-2283-2

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  • DOI: https://doi.org/10.1007/s10549-012-2283-2

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