Bystander activity of Ad-mda7: Human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism

Chada, Sunil; Mhashilkar, Abner M.; Ramesh, Rajagopal; Mumm, John B.; Sutton, R. Bryan; Bocangel, Dora; Zheng, Mingzhong; Grimm, Elizabeth A.; Ekmekçioglu, Sühendan

doi:10.1016/j.ymthe.2004.08.020

Cited by 97 publications

(119 citation statements)

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“…Differences in tumor size were analyzed for significance by the Student's t-test. Enhanced in vitro growth inhibitory and cytotoxic activity of Ad-mda7 and Herceptin in Her-2 þ breast cancer cells The antiproliferative effects of Ad-mda7 in various cancer cell types have been demonstrated in previous studies; [16][17][18][19][20][21][22][24][25][26][27][28][29][30][31][32][33][34]36 and the relevance of these findings to the clinical setting is supported by in vivo lung and breast xenograft models. 17,21 To corroborate that the Her-2 receptors expressed by the breast cancer cells are functional, we evaluated cell death in MDA-MB-453 and MCF-7 lines treated with increasing amounts of Herceptin (0-100 mg/ ml).…”

Section: Discussionmentioning

confidence: 81%

“…[18][19][20][21][22][23]38 It is now known that mda-7 activates various signaling pathways in a cell-type-specific manner, and that these pathways ultimately converge on mitochondrial destruction and induction of apoptosis. 21,22,[24][25][26][27][28][29][30] However, in spite of its clear tumor-suppressive effects, the mechanisms by which Ad-mda7 induces cytotoxicity have not been fully characterized. Our group has previously demonstrated that Ad-mda7, as a single agent therapy, induces apoptosis and inhibits growth in pancreatic, lung and breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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The melanoma differentiation-associated gene-7 (mda-7) is a member of the interleukin-10 cytokine family and a novel tumor suppressor gene. Adenoviral-mediated mda-7 (Ad-mda7) gene transfer has tumor-specific growth inhibitory and proapoptotic effects in a broad spectrum of cancer cells. In breast cancer cells, adenoviral-induced mda-7 expression triggers antiproliferative effects by downregulation of survival signals, such as Bcl-2 and Akt. The anti-human epidermal growth factor receptor-2 (Her-2) monoclonal antibody, Trastuzumab (Herceptin), increases the sensitivity of Her-2/neu-overexpressing breast cancer cells to chemotherapeutic agents and radiotherapy. In this study, we evaluate the effects of treatment with Ad-mda7 and Herceptin combination therapy in a panel of Her-2/neu-overexpressing cell lines, and in established tumors in nude mice. Compared to individual treatments, the combination of Ad-mda7 and Herceptin elicits supra-additive antitumor activity in Her-2/neuoverexpressing tumor cell lines: increased cell death, cell cycle block and apoptosis. The Ad-mda7 and Herceptin interaction was shown to be synergistic by isobologram analysis. Ad-mda7 does not alter cell surface Her-2/neu levels, but the combination of Ad-mda7 þ Herceptin results in increased expression of cell surface E-cadherin with concomitant translocation of b-catenin from the nucleus to the cell membrane. In vivo, the combination of Ad-mda7 and Herceptin showed significantly increased antitumor activity (Po0.003) against Her-2/neu-overexpressing tumors. These data suggest that the combination of Ad-mda7 with Herceptin may be a novel therapy for breast cancer patients whose tumors overexpress Her-2/neu. The observed synergistic effect may improve treatment options for otherwise poorly responsive, Her-2-positive, breast cancer patients. Cancer Gene Therapy (2006) 13, 958-968.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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“…These include inhibition of tumor cell invasion and migration, 34,35 potent antiangiogenic effects, 36,37 immune stimulatory activity 38,39 and direct bystander cytotoxicity. 40 In recent studies, a phase I clinical trial was initiated using intratumoral injections of nonreplicating adenovirus vector harboring the mda-7/IL-24 gene (Admda-7; INGN 241). INGN 241 can induce apoptosis in a large part of tumor volume following a single intratumoral injection.…”

Section: Discussionmentioning

confidence: 99%

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

Zhao

Dong

et al. 2006

Cancer Gene Ther

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Melanoma differentiation associated gene-7 (Mda-7)/IL-24 was previously cloned into ZD55 (an adenovirus with E1B55 deleted) to form ZD55-IL-24, which had much better antitumor effect than Ad-IL-24. According to its good antitumor properties, ZD55-IL-24 has been used in preclinical studies. But ZD55-IL-24 alone still could not completely eradicate established tumors in all nude mice. It was reported that IL-24 could induce and enhance the activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (a member of tumor necrosis factor (TNF) superfamily). Accordingly, the combined use of ZD55-IL-24 and ZD55-TRAIL was carried out in this study. Treatment with both ZD55-IL-24 and ZD55-TRAIL could induce more significant apoptosis in cancer cells in vitro compared with ZD55-IL-24 or ZD55-TRAIL alone. The combination of the two replicative adenoviruses had better antitumor activity in vivo than that of single oncolytic adenovirus and led to complete eradication of xenograft tumors in all treated mice. Upregulation of TRAIL was observed in tumor cells infected with ZD55-IL-24 and studies of the apoptotic cascade regulators indicate that ZD55-IL-24 could further enhance the activation of apoptosis through the TNF family of death receptors. We demonstrated for the first time the potential therapeutic effect of combined ZD55-IL-24 with ZD55-TRAIL for the targeted therapy of cancer.

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“…These results indicate that the bystander effect is likely caused by secreted MDA-7/IL-24 protein and not by other secreted factor(s). It has been demonstrated that partially purified MDA-7/IL-24 protein, obtained from supernatants of HEK293 cells, induces apoptosis only in cancer cells in a receptordependent and STAT3-independent manner (29). A recent study demonstrated that purified MDA-7/IL-24 protein induces cell death in melanoma cells (29).…”

mentioning

confidence: 99%

“…It has been demonstrated that partially purified MDA-7/IL-24 protein, obtained from supernatants of HEK293 cells, induces apoptosis only in cancer cells in a receptordependent and STAT3-independent manner (29). A recent study demonstrated that purified MDA-7/IL-24 protein induces cell death in melanoma cells (29). However, a detailed analysis of the molecular mechanism underlying this effect was not performed.…”

mentioning

confidence: 99%

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

117

153

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A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an adenovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancerspecific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor ''bystander'' effect. The present studies reveal a provocative finding that recombinant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttranscriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phosphoeIF2␣) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.bystander antitumor activity ͉ endoplasmic reticulum stress ͉ reactive oxygen species ͉ mRNA stabalization ͉ cancer-specific killing

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Bystander activity of Ad-mda7: Human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism

Cited by 97 publications

References 37 publications

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

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