Background: DDT is a novel member of the MIF cytokine family with overlapping functions. Results: DDT is a direct HIF target gene that is expressed widely in renal carcinoma and contributes to tumorigenesis. Conclusion: DDT has greater tumor-promoting properties than MIF and may compensate for MIF inhibition. Significance: Efforts to inhibit MIF signaling in cancer need to target DDT as well.

The phosphorylated ribosomal protein S6 (pS6) is associated with the 40S ribosomal subunit in eukaryotes and is thought to play a role in RNA storage, degradation, and re-entry into translation. In this study, we found pS6 localized to granulovacuolar degeneration (GVD) within pyramidal neurons. Immunohistochemical analysis found nearly 20 fold more neurons contain pS6 positive granules in Alzheimer’s disease (AD) hippocampus compared with age-matched controls. Further, pS6-positive granules were more common in neurons not containing neurofibrillary tangles, were never associated with extracellular neurofibrillary tangles or in apoptotic neurons, and contained less RNA than neighboring pyramidal neurons not containing pS6-positive granules. In model systems, pS6 is a specific marker for stress granules, and another stress granule protein, p54/Rck we also found to be a component of GVD in the current study. Stress granules are transient, intracellular, dense aggregations of proteins and RNAs that accumulate as a stress response, protecting cells from apoptosis and inappropriate transcriptional activity, often described as a form of “molecular triage.” The RNA oxidation modification 8-hydroxyguanosine (8OHG) is strikingly increased in AD, yet this study reports that those neurons with pS6 granules display reduced RNA oxidation demonstrated by lower levels of 8OHG. Since chronic oxidative stress is central to AD pathogenesis, and RNA is a specific oxidative stress target and is intimately associated with stress granule biogenesis in model systems, we suggest that GVD in human brain parallel stress granules, and may in fact be more representative of early disease pathogenesis than traditionally believed. This proposed origin for GVD as a neuroprotective response, may represent a morphologic checkpoint between cell death and reversible cellular stress that proceeds in the absence of other inclusions.

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.

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