A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma
Zong Miao,
Lei Xu,
Wei Gu,
Yimin Ren,
Rong Li,
Shuai Zhang,
Chao Chen,
Hongxiang Wang,
Jing Ji,
Juxiang Chen
Affiliations
Zong Miao
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
Lei Xu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Wei Gu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Yimin Ren
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
Rong Li
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
Shuai Zhang
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
Chao Chen
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
Hongxiang Wang
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China; Corresponding author.
Jing Ji
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China; Corresponding author. Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Juxiang Chen
Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China; Corresponding author.
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.
