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

V. Valero, H. Wingate, S. Chada, Y. Liu, F. Palalon, Gordon Mills, K. Keyomarsi, K. K. Hunt

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)510-519
Number of pages10
JournalCancer Gene Therapy
Volume18
Issue number7
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

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Cell Cycle Checkpoints
Down-Regulation
Apoptosis
Breast Neoplasms
Caspases
Melanoma
Cell Line
Estrogen Receptor beta
Neoplasms
Protein Array Analysis
Cyclin-Dependent Kinases
MCF-7 Cells
Fluorescence Microscopy
Confocal Microscopy
Genes
Cell Cycle
Up-Regulation
Western Blotting
Phenotype
Growth

Keywords

  • breast cancer and AKT
  • IL-24
  • MDA-7

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells. / Valero, V.; Wingate, H.; Chada, S.; Liu, Y.; Palalon, F.; Mills, Gordon; Keyomarsi, K.; Hunt, K. K.

In: Cancer Gene Therapy, Vol. 18, No. 7, 01.07.2011, p. 510-519.

Research output: Contribution to journalArticle

Valero, V, Wingate, H, Chada, S, Liu, Y, Palalon, F, Mills, G, Keyomarsi, K & Hunt, KK 2011, 'MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells', Cancer Gene Therapy, vol. 18, no. 7, pp. 510-519. https://doi.org/10.1038/cgt.2011.20
Valero, V. ; Wingate, H. ; Chada, S. ; Liu, Y. ; Palalon, F. ; Mills, Gordon ; Keyomarsi, K. ; Hunt, K. K. / MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells. In: Cancer Gene Therapy. 2011 ; Vol. 18, No. 7. pp. 510-519.
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