Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1alpha is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1alpha protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1alpha resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis.

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Sodium tolerance in yeast is enhanced by continuous activation of calcineurin, a Ca2؉ /calmodulin-dependent protein phosphatase that is required for modulation of the Na ؉ efflux mechanism. We isolated several salt-tolerant mutations with the treatment of ethylmethane sulfonate under high salt stress. One of the mutations was mapped in the PMR1 gene. Pmr1p, the P-type Ca 2؉ -ATPase in the Golgi apparatus, regulates a cytosolic Ca 2؉ level in various responses. Cytosolic Ca 2؉ concentration in the pmr1 mutant is highly maintained, and thus calcineurin is activated continuously. The treatment of FK506, a specific inhibitor of calcineurin, abolishes the salt-tolerant phenotype of the pmr1 mutant. Activated calcineurin induces the expression of PMR2, encoding the P-type Na ؉ -ATPase, through the specific transcription factor, Tcn1p/Crz1p. Also, expression of the PMR2::lacZ reporter gene in the pmr1 mutant was higher than that in wild type. We propose that the pmr1 mutation confers salt tolerance through continuous activation of calcineurin and that Pmr1p might act as a major Ca 2؉ -ATPase under high salt stress.

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Angiogenesis is considered to be an integral process to the growth and spread of solid tumors. Anti-angiogenesis therapy recently has been found to be one of the most promising anti-cancer therapeutic strategies. In this study, we provide several lines of evidences showing that KR-31831, a new benzopyran derivative, has anti-angiogenic activities. KR-31831 inhibited the proliferation, migration, invasion and tube formation of bovine aortic endothelial cells (BAECs), and suppressed the release of matrix metalloproteinase-2 (MMP-2) of BAECs. KR-31831 also inhibited in vivo angiogenesis in mouse Matrigel plug assay. Furthermore, the mRNA expressions of basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-2 (FGFR-2), and vascular endothelial growth factor receptor-2 (VEGFR-2) were decreased by KR-31831. Taken together, these results suggest that KR-31831 acts as a novel angiogenesis inhibitor and might be useful for treating hypervascularized cancers.