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MIF Antagonist (CPSI-1306) Protects against UVB-Induced Squamous Cell Carcinoma

2014; American Association for Cancer Research; Volume: 12; Issue: 9 Linguagem: Inglês

10.1158/1541-7786.mcr-14-0255-t

1557-3125

Priyadharsini Nagarajan, Kathleen L. Tober, Judith A. Riggenbach, Donna F. Kusewitt, Amy M. Lehman, Thais M. Sielecki, James R. Pruitt, Abhay R. Satoskar, Tatiana M. Oberyszyn,

Nuclear Receptors and Signaling

Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non-tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306-treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.