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


CONCLUSIONS
Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Priyadharsini
P
Nagarajan
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Kathleen L
KL
Tober
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Judith A
JA
Riggenbach
Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
Donna F
DF
Kusewitt
Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Amy M
AM
Lehman
Cytokine PharmaSciences, King of Prussia, Pennsylvania.
Thais
T
Sielecki
Cytokine PharmaSciences, King of Prussia, Pennsylvania.
James
J
Pruitt
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Abhay R
AR
Satoskar
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio. oberyszyn.1@osu.edu.
Tatiana M
TM
Oberyszyn
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D007555:Isoxazoles / Q000008:administration & dosage*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage*; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays
C000598334:CPSI-1306; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D009025:Morpholines; D016159:Tumor Suppressor Protein p53; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human