title: Macrophage Migration Inhibitory Factor Secretion Is Induced by Ionizing Radiation and Oxidative Stress in Cancer Cells.
abstract: The macrophage migration inhibitory factor (MIF) has been increasingly implicated in cancer development and progression by promoting inflammation, angiogenesis, tumor cell survival and immune suppression. MIF is overexpressed in a variety of solid tumor types in part due to its responsiveness to hypoxia inducible factor (HIF) driven transcriptional activation. MIF secretion, however, is a poorly understood process owing to the fact that MIF is a leaderless polypeptide that follows a non-classical secretory pathway. Better understanding of MIF processing and release could have therapeutic implications. Here, we have discovered that ionizing radiation (IR) and other DNA damaging stresses can induce robust MIF secretion in several cancer cell lines. MIF secretion by IR appears independent of ABCA1, a cholesterol efflux pump that has been implicated previously in MIF secretion. However, MIF secretion is robustly induced by oxidative stress. Importantly, MIF secretion can be observed both in cell culture models as well as in tumors in mice in vivo. Rapid depletion of MIF from tumor cells observed immunohistochemically is coincident with elevated circulating MIF detected in the blood sera of irradiated mice. Given the robust tumor promoting activities of MIF, our results suggest that an innate host response to genotoxic stress may mitigate the beneficial effects of cancer therapy, and that MIF inhibition may improve therapeutic responses.
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.|Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Yashi
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Vinay
authors.initials: V
authors.lastname: Pasupuleti
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Weinan
authors.initials: W
authors.lastname: Du
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Welford
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000097:blood / Q000532:radiotherapy; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species