[en] Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-α 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-α can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-α are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-κB (NF-κB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IκB 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-α NF-κB 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-α-induced NF-κB 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-α inhibition. Future studies will address this hypothesis.
Disciplines :
Oncology
Author, co-author :
Romano, Simona
D'arrigo, Paolo ; Université de Liège - ULiège > I3-Virology and Immunology
Tufano, Martina
Staibano, Stefania
Rea, Anna
Merolla, Francesco
Ilardi, Gennaro
Petrella, Antonello
Romano, Maria F.
Language :
English
Title :
TRAF2 and FKBP51 as possible markers for identification of suitable melanoma tumors for tumor necrosis factor-α inhibition.
Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants-past, present and future. Cytokine Growth Factor Rev 2014; 25:453-472.
Cornett WR, McCall LM, Petersen RP, Ross MI, Briele HA, Noyes RD, et al. Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor. American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 2006; 24:4196-4201.
van Horssen R, Ten Hagen TL, Eggermont AM. TNF-Alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist 2006; 11:397-408.
Bertrand F, Montfort A, Marcheteau E, Imbert C, Gilhodes J, Filleron T, et al. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun 2017; 8:2256.
Gray-Schopfer VC, Karasarides M, Hayward R, Marais R. Tumor necrosis factor-Alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res 2007; 67:122-129.
Sun SC, Ley SC. New insights into NF-kappaB regulation and function. Trends Immunol 2008; 29:469-478.
Kashani-Sabet M, Shaikh L, Miller JR III, Nosrati M, Ferreira CM, Debs RJ, Sagebiel RW. NF-kappa B in the vascular progression of melanoma. J Clin Oncol 2004; 22:617-623.
Romano S, Xiao Y, Nakaya M, DAngelillo A, Chang M, Jin J, et al. FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma. Nucleic Acids Res 2015; 43:6983-6993.
Romano S, DAngelillo A, Romano MF. Pleiotropic roles in cancer biology for multifaceted proteins FKBPs. Biochim Biophys Acta 2015; 1850:2061-2068.
Mascolo M, Romano MF, Ilardi G, Romano S, Baldo A, Scalvenzi M, et al. Expression of FK506-binding protein 51 (FKBP51) in Mycosis fungoides. J Eur Acad Dermatol Venereol 2018; 32:735-744.
Romano S, DAngelillo A, Pacelli R, Staibano S, De Luna E, Bisogni R, et al. Role of FK506 binding protein 51 (FKBP51) in the control of apoptosis of irradiated melanoma cells. Cell Death Differ 2010; 17:145-157.
Hartig SM. Basic image analysis and manipulation in ImageJ. J Curr Protoc Mol Biol 2013; Chapter 14:Unit14.15.
Costabile V, Duraturo F, Delrio P, Rega D, Pace U, Liccardo R, et al. Lithium chloride induces mesenchymal-To-epithelial reverting transition in primary colon cancer cell cultures. Int J Oncol 2015; 46:1913-1923.
DArrigo P, Russo M, Rea A, Tufano M, Guadagno E, Del Basso De Caro ML, et al. A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma. Oncotarget 2017; 8:68291-68304.
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. A physical and functional map of the human TNF-Alpha/NF-kappaB signal transduction pathway. Nature Cell Biol 2004; 6:97-105.
Thomas GS, Zhang L, Blackwell K, Habelhah H. Phosphorylation of TRAF2 within Its RING domain inhibits stress-induced cell death by promoting IKK and suppressing JNK activation. Cancer Res 2009; 69:3665-3672.