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

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.

Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma

“…Ad-mda-7 also showed slight decrease of Erk1/2 signaling and p53 expression levels, but their functional roles in cell death could be minimal. In contrast to the present study, previous studies demonstrated that Ad-mda-7 downregulated the Akt pathways [11][12][13] and enhanced the Erk1/2 pathways. 14 Nevertheless, Pataer et al 15 demonstrated that Ad-mda-7 upregulated phosphorylation of Akt but decreased total Akt levels as we observed.…”

Reversal Effect of Melanoma Differentiation Associated Gene‐7/Interleukin‐24 on Multidrug Resistance in Human Hepatocellular Carcinoma Cells

“…Accumulative reports have shown that mda-7/IL-24 displays antitumor properties and inhibits cancer cell growth by inducing apoptosis and arresting cell cycle (Wang et al, 2007;Dent et al, 2010;Otkjaer et al, 2010;Wang et al, 2010;Valero et al, 2011). Previous studies have shown that LRP, MDR1, and MRP1 play important roles in tumor MDR.…”

“…It binds to cell surface receptors to induce transcriptional activation of signal transducers and activators of transcription 3-phosphorylation (Dumoutier et al, 2001;Zhang et al, 2011a). Previous studies have shown that mda-7/IL-24 inhibits cell growth and induces apoptosis in melanoma, lung cancer, and other tumor types (Dent et al, 2010;Otkjaer et al, 2010;Wang et al, 2010;Wei et al, 2010;Xiao et al, 2010;Bhutia et al, 2011;Valero et al, 2011). It has also been shown that mda-7/IL-24 could reduce angiogenesis in tumors (Wang et al, 2007;Chang et al, 2009), suggesting that it is a tumor suppressor gene.…”

Stabilization of MDA-7/IL-24 for colon cancer therapy

“…Loss of IL-24 expression has been found with the progression of several cancers, such as melanoma [7]. Although IL-24 exhibits interesting properties through various signaling pathways [8][9][10][11][12][13][14][15][16], the molecular mechanisms involved in the regulation of IL-24 expression and activation and its anticancer activity are not yet completely understood [17,18]. Recombinant IL-24 induces apoptosis in a broad range of human cancers including colorectal cancer (CRC), with no significant toxicity to normal cells [19].…”