alexa Glucose is a key regulator of VEGFR2 KDR in human epithelial ovarian carcinoma cells.


Journal of Cancer Science & Therapy

Author(s): Adham SA, Coomber BL

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Abstract Epithelial ovarian cancer (EOC) is a serious gynecological cancer and there may be an increased risk of developing EOC in women with metabolic disruptions such as diabetes-related hyperglycemia, obesity or high glycemic load. Upregulation of vascular endothelial growth factor (VEGF) in ischemic conditions (e.g. hypoxia, hypoglycemia) induces tumor angiogenesis. We previously showed that EOC cells employ an autocrine VEGF/VEGFR2 signaling loop. Here we demonstrate the influence of glucose levels on VEGF and its receptors in the human EOC lines OVCAR-3 and CAOV-3. Glucose (but not pyruvate) deprivation induced significant increase in VEGF transcription and secretion, but a rapid reduction in VEGFR2 protein synthesis and glycosylation, combined with a reduction in co-receptor neuropilin-1 (NRP-1) protein levels. In contrast, mRNA for KDR and NRP-1 was increased upon glucose depletion suggesting a mechanism of feed back upon protein reduction. The addition of the proteosome inhibitor epoxomycin restored VEGFR2 under glucose free conditions, suggesting degradation as the main mechanism of VEGFR2 reduction and transcriptional activation through the unfolded protein response (UPR) which was activated in glucose-starved cells through the upregulation of the Endoplasmic reticulum chaperon GRP-78. Our finding that glucose can regulate VEGF/VEGFR2 levels suggests that initiation and/or progression of ovarian surface epithelial cells towards a neoplastic phenotype might be modulated by dietary conditions, and that a patient's metabolic status may alter the effectiveness of the known anti-angiogenic therapies. This information provides opportunities to explore the biology of EOC progression and improve our understanding of the mechanistic insight of this interesting regulatory effect. This article was published in Biochem Biophys Res Commun and referenced in Journal of Cancer Science & Therapy

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