Abstract
BackgroundHypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor-1α (HIF-1α) is observed, and can increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis. Zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, is potential to inhibit tumor proliferation and progression. However, the mechanism of ZnPP in inhibition of tumor is not completely clear. We hypothesize that ZnPP may modulate HIF-1α through inhibiting HO-1, and then inhibit angiogenesis and tumor progression. This study aimed to dissect the mechanism of ZnPP in tumor suppression.ResultsWe observed the amount of VEGF was increased in the sera of the colorectal cancer (CRC) patients (n = 34, p < 0.05). Furthermore, increased VEGF expression was also measured in colorectal cancer cells, HCT-15, culturing under mimicking hypoxic condition. It suggested that hypoxia induced VEGF production from cancer cells. VEGF production was significantly reduced from HCT-15 cells after exposure to HIF-1α inhibitor KC7F2, suggesting that HIF-1α regulated VEGF production. Moreover, we observed that the HO-1inhibitor ZnPP inhibited the expressions of HIF-1α and VEGF coupled with cell proliferations of HCT-15 cells, suggesting that ZnPP blocked HIF-1α expression, and then inhibited the consequent VEGF production. In the xenograft model, we also observed that the animals exposed to ZnPP displayed much smaller tumor nodules and less degree of angiogenesis with decreased expression of the angiogenesis marker, αvβ3 integrin, compared to that in normal control.ConclusionsThis study demonstrated that VEGF level in serum was elevated in the patients with CRC. The HO-1 inhibitor, ZnPP, possessed the properties of anti-tumor agent by decreasing HIF-1α levels, blocking VEGF production, impairing tumor angiogenesis, and inhibiting tumor growth.
Highlights
Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells
Zinc protoporphyrin (ZnPP) reduced tumor angiogenesis and tumor growth in HCT-15-induced xenografts We demonstrated that ZnPP-mediating reduction in HCT-15 proliferation combined with decreased vascular endothelial growth factor (VEGF) release, so we further liked to investigate the in vivo inhibitory potential of ZnPP on tumor and angiogenesis in animals suffered with cancers
In conclusion, this study demonstrated that ZnPP is a heme oxygenase-1 (HO-1) inhibitor, and a potential anti-tumor agent inhibiting tumor proliferation
Summary
Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Due to highly accelerated cell divisions and proliferations, tumor cells survive in the microenvironments with deprived oxygen termed as hypoxia, in which may elicit signals to form new blood vessels around tumors for providing additional oxygen and nutrient to tumors [1] Under this hypoxia condition, deprivation of oxygen in blood causes pathophysiologic consequences within tumor cells, leading to exacerbate tumor progression, tumor invasion and gain the resistance to apoptotic cell death program [2, 3]. Increased HIF-1α induced by hypoxia can commit the adaptive changes in gene expressions of tumor cells [2, 6, 7]. It suggests that HIF-1α is one of potential therapeutic targets in tumors
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