TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis
Authors
Liu, FeiyanHu, Xiaolin
Zimmerman, Mary
Waller, Jennifer L.
Wu, Ping
Hayes-Jordan, Andrea
Lev, Dina
Liu, Kebin
Issue Date
2011-01-17
Metadata
Show full item recordAbstract
nullBackground: 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):e16241ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0016241
Scopus Count
Related articles
- Oxaliplatin sensitizes human colon cancer cells to TRAIL through JNK-dependent phosphorylation of Bcl-xL.
- Authors: El Fajoui Z, Toscano F, Jacquemin G, Abello J, Scoazec JY, Micheau O, Saurin JC
- Issue date: 2011 Aug
- [Overcoming acquired resistance to tumor necrosis factor-related apoptosis-inducing ligand by Bcl-XL small interfering RNA in human colon cancer].
- Authors: Zhu HB, Huang XF, Hu JZ, Zhou W, Chen W, Chen LL, He C
- Issue date: 2008 Apr
- Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo.
- Authors: Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K
- Issue date: 2012 May 1
- Bcl-xL/Bax ratio is altered by IFNgamma in TNFalpha- but not in TRAIL-induced apoptosis in colon cancer cell line.
- Authors: Baillat G, Garrouste F, Remacle-Bonnet M, Marvaldi J, Pommier G
- Issue date: 2005 Aug 15
- Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria.
- Authors: Nagy K, Székely-Szüts K, Izeradjene K, Douglas L, Tillman M, Barti-Juhász H, Dominici M, Spano C, Luca Cervo G, Conte P, Houghton JA, Mihalik R, Kopper L, Peták I
- Issue date: 2006