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Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-?B pathway to induce metastatic potential.

ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been recognized as a promising target for cancer therapy because it can induce apoptotic cell death in tumor cells but not normal cells. Although TRAIL shows specific tumoricidal activity, resistance to TRAIL-induced apoptosis in some tumor cells has been considered a clinical obstacle of its application. It has been shown that TRAIL provides inflammatory signals that may contribute to the TRAIL-resistance of cancer cells; however, it is not known whether TRAIL itself is involved in malignant cancer cell behavior. In the present study, we examined the functional role of TRAIL in B16F10 mouse melanoma cells, which are totally insensitive to TRAIL-induced apoptosis. By establishing B16F10 cells stably expressing the nuclear factor-?B (NF?B)-luciferase reporter gene, we found that TRAIL can activate NF?B through its death receptor DR5 in B16F10 cells. Furthermore, TRAIL-DR5 interaction not only promoted malignant behaviors of B16F10 cells, such as cell proliferation and MMP-9 production, but also induced lung metastasis of B16F10 cells in vivo. These findings may imply a contrary role for the TRAIL-DR5 pathway in the inflammatory tumor microenvironment, in its ability to induce the metastatic potential of B16F10 melanoma cells instead of inducing apoptosis.

SUBMITTER: Takahashi K

PROVIDER: S-EPMC7657238 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-κB pathway to induce metastatic potential.

Takahashi Kei K Takeda Kazuyoshi K Saiki Ikuo I Irimura Tatsuro T Hayakawa Yoshihiro Y

Cancer science 20130228 5

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been recognized as a promising target for cancer therapy because it can induce apoptotic cell death in tumor cells but not normal cells. Although TRAIL shows specific tumoricidal activity, resistance to TRAIL-induced apoptosis in some tumor cells has been considered a clinical obstacle of its application. It has been shown that TRAIL provides inflammatory signals that may contribute to the TRAIL-resistance of cancer cells; howev ...[more]

PMID: 23347256

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Project description:Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. METHODS; Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided.Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity.Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors.

Dataset Information

Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-?B pathway to induce metastatic potential.

Publications

Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-κB pathway to induce metastatic potential.

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