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.

Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

“…Whilst MIF plasma levels are higher in CLL (Reinart et al , ), our study found that intracellular levels are lower in CLL cells. MIF secretion is robustly induced by oxidative stress (Gupta et al , ), which is supported by our data showing that CLL cells have higher expression of several antioxidant species (e.g. TXNRD2, GSTP1, SOD1, TXN) and evidence from the literature showing that CLL cells have high levels of intracellular ROS species (Mayer et al , ).…”

CSF macrophage migration inhibitory factor levels did not predict steroid treatment response after optic neuritis in patients with multiple sclerosis

“…MIF has been found to play a role in a diverse range of physiological as well as pathological processes [ 29 ], so does not provide a specific physicochemical biomarker for MS-related disease processes, in particular MIF blood concentration [ 14 ]. Indeed, MIF may be secreted by a wide range of cells, including macrophages, T-cells, dendritic, endothelial, and epithelial cells [ 30 – 32 ] and it is constitutively expressed in cerebral and spinal neurons as well as in microglia [ 33 , 34 ]. Release and detection of MIF reveals activity pertaining to inflammation, chemotaxis, cell survival and proliferation [ 14 , 15 , 35 ].…”

“…In addition to its key role in diverse inflammatory processes, MIF may be secreted by tumors [ 30 , 36 ], and its potential as a (tumor) biomarker has also been investigated [ 35 , 37 ].…”

“…The processes of MIF secretion are not well-understood, because of its non-classical secretory pathway [ 30 , 32 ]. Evidence has been found that when MIF is secreted, it is initially stored in vesicles in certain cell types, prior to its release via an ATP-binding cassette transporter [ 32 , 36 ].…”

Expression pattern of miR-451 and its targetMIF(macrophage migration inhibitory factor) in colorectal cancer

“…To exert its effects, miR-451 targets several genes and the most significant target is MIF ( macrophage migration inhibitory factor ) 15 16. MIF protein is a proinflammatory cytokine that has association with pathogenesis of chronic inflammatory diseases,17 and many types of cancers 18 19. Recent studies have proven that MIF has the potential to act as a target against cancer as its expression in human cancers correlates positively with the tumour aggressiveness and metastatic potential 20–22…”