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Inhibition of the inflammatory cytokine TNF-? increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression.

ABSTRACT: Oncolytic adenoviruses show promise as a cancer treatment. However, they generate acute inflammatory responses with production of cytokines, including tumor necrosis factor-? (TNF-?). We investigated whether inhibition of TNF-? augments efficacy of the E1A CR2-deleted adenovirus dl922-947 in ovarian cancer. dl922-947 induced transcription of TNF-? and its downstream signaling targets interleukin-6 and -8 (IL-6 and IL-8) in ovarian cancer cells. In vitro, RNAi-mediated knockdown of TNF-? reduced production of multiple inflammatory cytokines after infection and increased ovarian cancer cell sensitivity to virus cytotoxicity, as did treatment with the anti-TNF-? antibody infliximab. In vivo, stable knockdown of TNF-? in IGROV-1 xenografts increased the anticancer activity of dl922-947. In addition, inhibition of TNF-? using monoclonal antibodies also improved dl922-947 efficacy. This increased efficacy resulted from suppression of cellular inhibitor of apoptosis-1 and -2 (cIAP1 and cIAP2) transcription in malignant cells and a consequent increase in caspase-mediated apoptosis. These findings suggest that TNF-? acts as a survival factor in adenovirus-infected cells. Combining TNF-? inhibition with oncolytic adenoviruses could improve antitumor activity in clinical trials.

SUBMITTER: Salako MA

PROVIDER: S-EPMC3048177 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Inhibition of the inflammatory cytokine TNF-α increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression.

Salako Michael A MA Kulbe Hagen H Ingemarsdotter Carin K CK Pirlo Katrina J KJ Williams Sarah L SL Lockley Michelle M Balkwill Frances R FR McNeish Iain A IA

Molecular therapy : the journal of the American Society of Gene Therapy 20101116 3

Oncolytic adenoviruses show promise as a cancer treatment. However, they generate acute inflammatory responses with production of cytokines, including tumor necrosis factor-α (TNF-α). We investigated whether inhibition of TNF-α augments efficacy of the E1A CR2-deleted adenovirus dl922-947 in ovarian cancer. dl922-947 induced transcription of TNF-α and its downstream signaling targets interleukin-6 and -8 (IL-6 and IL-8) in ovarian cancer cells. In vitro, RNAi-mediated knockdown of TNF-α reduced ...[more]

PMID: 21081903

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Project description:Background: One of the important pathogenesis of acute respiratory distress syndrome (ARDS) is the dysfunction of pulmonary microvascular endothelial barrier induced by a hyperinflammatory immune response. However, the potential mechanisms of such an imbalance in pulmonary microvascular endothelial cells (PMVECs) are not yet understood. Purpose: Explore the molecular mechanism of endothelial barrier dysfunction induced by inflammatory immune cytokines in ARDS, and find a therapeutic target for this syndrome. Methods: Rat PMVECs were cultured to form a monolayer. Immunofluorescence, flow cytometry, and Western blotting were selected to detect the distribution and the expression level of phosphorylated Ezrin protein and Ezrin protein. Transendothelial electrical resistance (TER) and transendothelial fluxes of fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) were utilized to measure the permeability of the cell monolayer. Ezrin short hairpin RNA (shRNA) and Ezrin 567-site threonine mutant (EzrinT567A) were used to examine the role of Ezrin protein and phosphorylated Ezrin protein in endothelial response induced by tumor necrosis factor-alpha (TNF-α), respectively. The function of focal adhesion kinase (FAK) and Ras homolog gene family, member A (RhoA) signaling pathways were estimated by inhibitors and RhoA/FAK shRNA in TNF-α-stimulated rat PMVECs. The activation of FAK and RhoA was assessed by Western blotting or pull-down assay plus Western blotting. Results: The TER was decreased after TNF-α treatment, while the Ezrin protein phosphorylation was increased in a time- and dose-dependent manner. The phosphorylated Ezrin protein was localized primarily at the cell periphery, resulting in filamentous actin (F-actin) rearrangement, followed by a significant decrease in TER and increase in fluxes of FITC-BSA. Moreover, FAK and RhoA signaling pathways were required in the phosphorylation of Ezrin protein, and the former positively regulated the latter. Conclusion: The phosphorylated Ezrin protein was induced by TNF-α via the FAK/RhoA signaling pathway leading to endothelial hyperpermeability in PMVECs.

Dataset Information

Inhibition of the inflammatory cytokine TNF-? increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression.

Publications

Inhibition of the inflammatory cytokine TNF-α increases adenovirus activity in ovarian cancer via modulation of cIAP1/2 expression.

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