Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2

Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1 alpha (HIF-1 alpha). In the current study, we investigated As(III) effects on HIF-1 alpha under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1 alpha protein levels under normoxia while the hypoxia-mediated induction of HIF1 alpha was reduced. Thereby, the As(III) effects on HIF-1 alpha were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1 alpha protein stability. In line, the different effects of As(III) via participation of HIF-1 alpha and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1 alpha abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1 alpha under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions. As(III) increased HIF-1 alpha under normoxia but reduced its hypoxia-dependent induction. The As(III) effects on HIF-1 alpha were dependent on ROS, NOX4, PI3K/Akt, and ERK1/2. The As(III) effects under normoxia involved transcriptional regulation via Nrf2. Knockdown of Nrf2 and HIF-1 alpha abolished As(III) effects in tube formation assays. The data may partially explain As(III)'s carcinogenic and anti-carcinogenic actions.