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Published on: September 7, 2013
MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma
Priyadharsini Nagarajan1, Kathleen L Tober1, Judith A Riggenbach1
1Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Unlabelled:
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.
Implications:
Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.
Insights
Inhibiting macrophage migration inhibitory factor (MIF) with CPSI-1306 reduced UVB-induced skin inflammation and squamous cell carcinoma development in mice. This suggests MIF is a promising target for preventing sun damage and skin cancer.
Area of Science:
- Dermatology
- Immunology
- Oncology
Background:
- Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine linked to inflammatory diseases and skin cancers.
- UVB radiation is a known cause of skin inflammation and squamous cell carcinoma (SCC).
Purpose of the Study:
- To investigate if inhibiting MIF can prevent UVB-induced skin inflammation and squamous carcinogenesis.
- To evaluate the efficacy of a small-molecule MIF inhibitor, CPSI-1306, in a mouse model.
Main Methods:
- Mice were treated with CPSI-1306 before and after UVB exposure.
- Skin changes, cell proliferation, apoptosis, DNA repair, and tumor development were assessed.
Main Results:
- CPSI-1306 reduced acute UVB-induced skin inflammation, increased keratinocyte apoptosis, and enhanced DNA repair.
- MIF inhibition slowed tumor development, reduced tumor burden, and prevented progression to invasive SCC.
- CPSI-1306 decreased p53 foci and Ki67 proliferation in UVB-exposed skin.
Conclusions:
- MIF inhibition is a viable strategy for preventing UVB-induced skin damage and SCC.
- Targeting MIF may offer a novel approach for skin cancer prevention.
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