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MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells

Cancer Gene Therapy volume 18, pages 510–519 (2011)Cite this article

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Abstract

The melanoma differentiation-associated gene-7 (mda-7) is a known mediator of apoptosis in cancer cells but not in normal cells. We hypothesized that MDA-7 interferes with the prosurvival signaling pathways that are commonly altered in cancer cells to induce growth arrest and apoptosis. We also identified the cell signaling pathways that are antagonized by MDA-7 leading to apoptosis. Using an adenoviral expression system, mda-7 was introduced into the breast cancer cell lines SKBr3, MCF-7 and MDA-MB-468, each with a different estrogen receptor (ER) and HER-2 receptor status. Downstream targets of MDA-7 were assessed by reverse phase protein array analysis, western blot analysis and immunofluorescence confocal microscopy. Our results show that MDA-7-induced apoptosis was mediated by caspases in all cell lines tested. However, MDA-7 modulates additional pathways in SKBr3 (HER-2 positive) and MCF-7 (ER positive) cells including downregulation of AKT-GSK3β and upregulation of cyclin-dependent kinase inhibitors in the nucleus. This leads to cell cycle arrest in addition to apoptosis. In conclusion, MDA-7 abrogates tumor-promoting pathways including the activation of caspase-dependent signaling pathways ultimately leading to apoptosis. In addition, depending on the phenotype of the breast cancer cell, MDA-7 modulates cell cycle regulating pathways to mediate cell cycle arrest.

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Acknowledgements

This work was supported in part by a grant from the Susan G. Komen Breast Cancer Foundation, PDF0504074, awarded to KKH.

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Author notes

  1. V Valero and H Wingate: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V Valero III, H Wingate, Y Liu, F Palalon & K K Hunt

  2. Intrexon Corporation, Blackburg, VA, USA

    S Chada

  3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Mills

  4. Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Keyomarsi

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  1. V Valero III
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Correspondence to K K Hunt.

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Valero, V., Wingate, H., Chada, S. et al. MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells. Cancer Gene Ther 18, 510–519 (2011). https://doi.org/10.1038/cgt.2011.20

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  • DOI: https://doi.org/10.1038/cgt.2011.20

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