Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-β (Aβ)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of Aβ/CTF expression and not altered by α-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of Aβ/CTFs and suppressed by α-tocopherol. α-tocopherol cytoprotection was accompanied by decreased Aβ/CTF aggregation. G also promoted Aβ/CTF aggregation but by mechanisms unaffected by α-tocopherol treatment. Our findings showed that Aβ/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by α-tocopherol. Moreover, our results suggest that while intracellular aggregation of Aβ/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated Aβ/CTFs does not invariably lead to cytotoxicity.
Epidemiologic evidence implicates cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid b peptide. The product of the oxygenation of arachidonic acid by the cyclooxygenases, prostaglandin H 2 (PGH 2 ), rearranges non-enzymatically to several prostaglandins, including the highly reactive c-keto aldehydes, levuglandins E 2 and D 2 . We demonstrate that PGH 2 markedly accelerates the formation of dimers and higher oligomers of amyloid b 1)42 . This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking cyclooxygenase activity to the formation of oligomers of amyloid b.
Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.
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