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Updated: Jun 24, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma
1Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China.
Abstract:
Temozolomide (TMZ) is a widely utilized chemotherapy treatment for patients with glioblastoma (GBM), although drug resistance constitutes a major therapeutic hurdle. Emerging evidence suggests that ferroptosis-mediated therapy could offer an appropriate alternative treatment option against cancer cells that are resistant to certain drugs. However, recurrent gliomas display robust ferroptosis resistance, although the precise mechanism of resistance remains elusive. In the present work, we report that proline rich protein 11 (PRR11) depletion significantly sensitizes GBM cells to TMZ by inducing ferroptosis. Mechanistically, PRR11 directly binds to and stabilizes dihydroorotate dehydrogenase (DHODH), which leads to glioma ferroptosis-resistant in a DHODH-dependent manner in vivo and in vitro. Furthermore, PRR11 inhibits HERC4 and DHODH binding, by suppressing the recruitment of E3 ubiquitin ligase HERC4 and polyubiquitination degradation of DHODH at the K306 site, which maintains DHODH protein stability. Importantly, downregulated PRR11 increases lipid peroxidation and alters DHODH-mediated mitochondrial morphology, thereby promoting ferroptosis and increasing TMZ chemotherapy sensitivity. In conclusion, our results reveal a mechanism via which PRR11 drives ferroptosis resistance and identifies ferroptosis induction and TMZ as an attractive combined therapeutic strategy for GBM.
Insights
Proline rich protein 11 (PRR11) depletion sensitizes glioblastoma (GBM) cells to temozolomide (TMZ) by inducing ferroptosis. PRR11 stabilizes dihydroorotate dehydrogenase (DHODH), promoting ferroptosis resistance in GBM.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Temozolomide (TMZ) is a standard chemotherapy for glioblastoma (GBM), but drug resistance limits its efficacy.
- Ferroptosis, a regulated form of cell death, is a potential therapeutic strategy for drug-resistant cancers.
- Glioblastoma exhibits resistance to ferroptosis, with the underlying mechanisms largely unknown.
Purpose of the Study:
- To investigate the role of proline rich protein 11 (PRR11) in temozolomide (TMZ) resistance and ferroptosis in glioblastoma (GBM).
- To elucidate the molecular mechanism by which PRR11 influences ferroptosis and TMZ sensitivity in GBM.
Main Methods:
- Utilized cell lines and in vivo models of glioblastoma.
- Investigated the interaction between PRR11 and dihydroorotate dehydrogenase (DHODH).
- Assessed the impact of PRR11 depletion on ferroptosis, lipid peroxidation, and mitochondrial morphology.
- Examined the role of E3 ubiquitin ligase HERC4 in DHODH degradation.
Main Results:
- Depletion of PRR11 significantly sensitized GBM cells to TMZ by inducing ferroptosis.
- PRR11 directly binds to and stabilizes DHODH, conferring ferroptosis resistance in a DHODH-dependent manner.
- PRR11 inhibits HERC4-mediated ubiquitination and degradation of DHODH, maintaining DHODH protein stability.
- Downregulation of PRR11 increased lipid peroxidation and altered mitochondrial morphology, promoting ferroptosis and enhancing TMZ sensitivity.
Conclusions:
- PRR11 is a key driver of ferroptosis resistance in glioblastoma.
- PRR11 stabilizes DHODH, thereby inhibiting ferroptosis and conferring resistance to TMZ chemotherapy.
- Targeting PRR11 to induce ferroptosis, in combination with TMZ, represents a promising therapeutic strategy for GBM.
