Ferroptosis and PPAR-gamma in the limelight of brain tumors and edema

Frontiers in Oncology

Oncology

Ivana Mitrovic¹  Luka Zurabashvili²  Hans-Herbert Steiner³  Eduard Yakubov³  Alexander Hammer⁴  Nicolai Savaskan⁵  Daishi Chen⁶  Sebastian Schmid⁷  Marc Dahlmanns⁸  Jana Katharina Dahlmanns⁸ 

[1] Department of Cardiac Surgery, Bogenhausen Hospital, Munich, Germany;Department of Neurosurgery, Inova Medical Center, Tbilisi, Georgia;Department of Neurosurgery, Paracelsus Medical University, Nuremberg, Germany;Department of Neurosurgery, Paracelsus Medical University, Nuremberg, Germany;Center for Spine and Scoliosis Therapy, Malteser Waldkrankenhaus St. Marien, Erlangen, Germany;Department of Neurosurgery, University Medical School Hospital Universitätsklinikum Erlangen (UKER), Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany;Department of Public Health Neukölln, District Office Neukölln of Berlin Neukölln, Berlin, Germany;Department of Otorhinolaryngology, Shenzhen People's Hospital, Jinan University, Shenzhen, China;Department of Trauma, Orthopaedics, Plastic and Hand Surgery, University Hospital Augsburg, Augsburg, Germany;Institute for Physiology and Pathophysiology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany;

关键词: glioblastoma;    glutamate;    peritumoral edema;    SLC7A11;    ferroptosis;   

DOI  :  10.3389/fonc.2023.1176038

 received in 2023-02-28, accepted in 2023-07-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced neurodegeneration has been identified as glutamate. Glutamate promotes cell growth and proliferation in variety of tumor types. Intriguently, glutamate is also an excitatory neurotransmitter and evokes neuronal cell death at high concentrations. Even though glutamate signaling at the receptor and its downstream effectors has been extensively investigated at the molecular level, there has been little insight into how glutamate enters the tumor microenvironment and impacts on metabolic equilibration until recently. Surprisingly, the 12 transmembrane spanning tranporter xCT (SLC7A11) appeared to be a major player in this process, mediating glutamate secretion and ferroptosis. Also, PPARγ is associated with ferroptosis in neurodegeneration, thereby destroying neurons and causing brain swelling. Although these data are intriguing, tumor-associated edema has so far been quoted as of vasogenic origin. Hence, glutamate and PPARγ biology in the process of glioma-induced brain swelling is conceptually challenging. By inhibiting xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated. This review sheds light on the role of glutamate in brain tumors presenting the conceptual challenge that xCT disruption causes ferroptosis activation in malignant brain tumors. Thus, interfering with glutamate takes center stage in forming the basis of a metabolic equilibration approach.

【 授权许可】

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Copyright © 2023 Yakubov, Schmid, Hammer, Chen, Dahlmanns, Mitrovic, Zurabashvili, Savaskan, Steiner and Dahlmanns