Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α

Abstract

Concerns were increasingly raised that several types of cancers overexpressed the nuclear factor erythroid 2-related factor 2 (Nrf2), which contributed strikingly to cancer biological capabilities and chemoresistance. However, the role of Nrf2 in the tumor vascular biology had yet to be mechanistically determined. Here, we investigated the involvement of Nrf2 in glioblastoma (GB) angiogenesis in hypoxia. First, we detected the overexpression of Nrf2 and correlated its protein level with microvessel density (MVD) in human GB tissues. Then, we established the stable RNAi-mediated Nrf2-knockdown cells and mimicked hypoxic condition in vitro. The knockdown of Nrf2 inhibited cell proliferation in vitro and suppressed tumor growth in mouse xenografts with a concomitant reduction in VEGF expression and MVD. Similar antiangiogenic effects were documented in endothelial tube formation assays. The downregulation of Nrf2 in glioma cells led to much lower accumulation of HIF-1α protein and limited expression of VEGF and other HIF-1α target genes in mimicking hypoxia. Mechanistic investigations suggested that HIF-1α degradation during hypoxia could be attributed to reduced mitochondrial O2 consumption in Nrf2-inhibited cells. It can be concluded that Nrf2, with its capacity for affecting the protein level of HIF-1α expression, has good reasons to be considered as a critical transcription factor for controlling glioma angiogenesis.

Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A

“…The regulation of HIF-1α by Nrf2 has been investigated in tumor angiogenesis. Suppression of Nrf2 inhibited HIF-1α and resulted in a reduction of VEGF and blood vessel formation in human glioma cells (17) and colon cancer cells (13). Reduced mitochondrial O 2 consumption accounts for the degradation of HIF-1α in Nrf2-deficient cancer cells.…”

“…We next investigated the role of Nrf2 on reparative angiogenesis in the ischemic retina. Nrf2 has been found to play an important role in angiogenesis in other contexts, both with respect to vascular development (12) and pathologic setting, such as tumor angiogenesis (13,17). To determine the importance of Nrf2 in ischemic retina, we compared wild-type (Nrf2…”

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage

“…Cells were cultured as monolayers in Ham's F12 medium supplemented with 10% FBS and antibiotics. Primary mouse alveolar epithelial cells were prepared from C57BL/6 mice as reported previously (26), with some modification (see the online supplement for details).…”

Expression of NF‑E2‑related factor 2 in a rat dural arteriovenous fistula model

“…However, the function of Nrf2 action may be much broader since it also regulates angiogenesis; for example, it may promote the formation of blood vessels to protect the retina from oxidative injury that occurs following hyperoxic stimulation (42). Furthermore, it has been demonstrated that downregulation of Nrf2 inhibits cancer cell vasculogenesis and migration in vivo and in vitro (21)(22)(23). These results indicate that the Nrf2/ARE signaling pathway may potentially contribute to the growth of DAVFs through the angiogenesis induced by VH.…”

“…Nrf2 contributes to the protection of tissues from damage induced by the outside environment, including damage arising from inflammation, trauma, ischemia, hemorrhage and cancer (18,19). Other studies have identified an association between Nrf2 and angiogenesis (20) and it was demonstrated that the absence of Nrf2 may suppress cancer cell angiogenesis and migration in vivo and in vitro (21)(22)(23). However, the association between DAVF and Nrf2 in the pathogenesis of DAVF remains unclear.…”