HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis

Abstract

Patients with glioblastoma (GBM) have poor prognosis and limited treatment options, largely due to therapy resistance upon the induction of apoptosis. Ferroptosis emerges as a potential antineoplastic strategy to bypass apoptosis resistance in traditional therapeutics. Hypoxia is a fundamental hallmark of GBM and hypoxia-inducible factor (HIF) is the main regulator of hypoxia response, however, the role of HIF has not been sufficiently explored in GBM. Herein, we first discovered that amplifying HIF signals by the prolyl hydroxylase (PHD) inhibitor roxadustat significantly suppressed GBM cell growth in vitro and in vivo, especially when the cells were resistant to temozolomide (TMZ). The accumulation of lipid peroxidation and cellular iron in GBM cells following roxadustat treatment indicated that the cells underwent ferroptosis, which was also supported by morphological changes in mitochondrial ultrastructure and immunogenic signals release. Moreover, in vivo studies further confirmed the ferroptosis induction and verified that roxadustat significantly prolonged survival of the mice harboring chemoresistant GBM without visible organ toxicity. Finally, we proved that the ferroptosis induction by roxadustat is HIF-α independent, especially activation of HIF-2α upregulating lipid regulatory genes was revealed to be mainly responsible for the enhanced lipid peroxidation. Altogether, our study provided novel evidence that amplifying HIF signals induced ferroptosis in chemoresistant GBM cells and suppressed the tumor growth in vivo, highlighting that ferroptosis induction by targeting HIF-α might provide new approaches to improve GBM treatment.

Ferroptosis Regulated by Hypoxia in Cells

“…In renal clear-cell carcinomas, HIF-2α activates HILPDA , which selectively enriches PUFA to promote lipid peroxidation and GPX4 inhibitor (RSL3, ML210, or ML162)-induced ferroptosis [ 61 ]. In glioblastoma (GBM), HIF-2α induced by the prolyl hydroxylase (PHD) inhibitor roxadustat, upregulated ferroptosis regulatory genes such as ACSL4 , PTGS2 , and CHAC1 , to enhance lipid peroxidation and erastin-induced ferroptosis, leading to the suppression of GBM cell growth in vitro and in vivo [ 118 ]. Another report showed that HIF-2α upregulated genes involved in lipid and iron metabolism in both colorectal cancer (CRC) cells and colon tumors in mice, which result in the cells being susceptible to ferroptosis induced by dimethyl fumarate [ 119 ].…”

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

“…Hypoxia is chronic in most tumors, and this condition is often exploited by cancer cells to sustain proliferation, metabolism, tumor invasion, and metastasis ( Yang et al, 2020 ). In this context, a key role is played by HIF1, a transcription factor activated by low oxygen and frequently overexpressed in cancer ( Su et al, 2022 ). Interestingly, HIF1 inhibits ferroptosis by: i) upregulating SCD1 to increase MUFA synthesis; ii) inhibiting the expression of ACSL4 to reduce Lipid-ROS generation, and iii) inhibiting the degradation of SLC7A11 ( Su et al, 2022 ).…”

“…In this context, a key role is played by HIF1, a transcription factor activated by low oxygen and frequently overexpressed in cancer ( Su et al, 2022 ). Interestingly, HIF1 inhibits ferroptosis by: i) upregulating SCD1 to increase MUFA synthesis; ii) inhibiting the expression of ACSL4 to reduce Lipid-ROS generation, and iii) inhibiting the degradation of SLC7A11 ( Su et al, 2022 ). Therefore, the reduced efficacy of radiation or drug-based therapies in solid tumors has been, at least in part, associated with HIF1-mediated inhibition of ferroptosis ( Wang et al, 2019 ; Su et al, 2022 ).…”

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma

“…In GBM, RSL3 was reported to drive ferroptosis by targeting GPX4 expression [ 7 ]. Su et al showed that roxadustat can induce ferroptosis in chemoresistant GBM cells [ 8 ]. GBM is highly aggressive, and epithelial–mesenchymal transition (EMT) processes are thought to play a crucial role in the spread and metastasis of GBM [ 9 ].…”