MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma

  • Mol Cancer Res. 2014 Sep;12(9):1292-302. doi: 10.1158/1541-7786.MCR-14-0255-T.
Priyadharsini Nagarajan  1 ,  Kathleen L Tober  1 ,  Judith A Riggenbach  1 ,  Donna F Kusewitt  2 ,  Amy M Lehman  3 ,  Thais Sielecki  4 ,  James Pruitt  4 ,  Abhay R Satoskar  1 ,  Tatiana M Oberyszyn  5
Affiliations
  • 1. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
  • 2. Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
  • 3. Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
  • 4. Cytokine PharmaSciences, King of Prussia, Pennsylvania.
  • 5. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio. [email protected].
PMID: 24850900 DOI: 10.1158/1541-7786.MCR-14-0255-T
Abstract

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.

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