TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis

Hdl Handle:
http://hdl.handle.net/10675.2/625
Title:
TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis
Authors:
Liu, Feiyan; Hu, Xiaolin; Zimmerman, Mary; Waller, Jennifer L.; Wu, Ping; Hayes-Jordan, Andrea; Lev, Dina; Liu, Kebin
Abstract:
null; Background: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.; Methodology/Principal Findings: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo.; Conclusions/Significance: TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.
Citation:
PLoS One. 2011 Jan 17; 6(1):e16241
Issue Date:
17-Jan-2011
URI:
http://hdl.handle.net/10675.2/625
DOI:
10.1371/journal.pone.0016241
PubMed ID:
21264227
PubMed Central ID:
PMC3022032
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Biochemistry and Molecular Biology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorLiu, Feiyanen_US
dc.contributor.authorHu, Xiaolinen_US
dc.contributor.authorZimmerman, Maryen_US
dc.contributor.authorWaller, Jennifer L.en_US
dc.contributor.authorWu, Pingen_US
dc.contributor.authorHayes-Jordan, Andreaen_US
dc.contributor.authorLev, Dinaen_US
dc.contributor.authorLiu, Kebinen_US
dc.date.accessioned2012-10-26T16:26:54Z-
dc.date.available2012-10-26T16:26:54Z-
dc.date.issued2011-01-17en_US
dc.identifier.citationPLoS One. 2011 Jan 17; 6(1):e16241en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21264227en_US
dc.identifier.doi10.1371/journal.pone.0016241en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/625-
dc.description.abstractnullen_US
dc.description.abstractBackground: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.en_US
dc.description.abstractMethodology/Principal Findings: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo.en_US
dc.description.abstractConclusions/Significance: TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.en_US
dc.rightsLiu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectDrug Discoveryen_US
dc.subjectImmunochemistryen_US
dc.subjectImmunologyen_US
dc.subjectImmune Systemen_US
dc.subjectCytokinesen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectCell Deathen_US
dc.subjectCell Growthen_US
dc.subjectCellular Stress Responsesen_US
dc.subjectMedicineen_US
dc.subjectGastroenterology and Hepatologyen_US
dc.subjectColonen_US
dc.subjectGastrointestinal Cancersen_US
dc.titleTNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosisen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3022032en_US
dc.contributor.corporatenameDepartment of Biochemistry and Molecular Biology-
dc.contributor.corporatenameDepartment of Biostatistics and Epidemiology-

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