Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-alpha is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-alpha can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-alpha are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-kappaB (NF-kappaB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IkappaB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-alpha NF-kappaB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-alpha-induced NF-kappaB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-alpha inhibition. Future studies will address this hypothesis.

TRAF2 and FKBP51 as possible markers for identification of suitable melanoma tumors for tumor necrosis factor-α inhibition

PETRELLA, Antonello
Membro del Collaboration Group
;
2019-01-01

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-alpha is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-alpha can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-alpha are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-kappaB (NF-kappaB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IkappaB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-alpha NF-kappaB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-alpha-induced NF-kappaB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-alpha inhibition. Future studies will address this hypothesis.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4719017
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