Hydrogen sulfide operates as a glioblastoma suppressor and is lost under high fat diet

Daniel J Silver; Justin D Lathia; Christopher Hine

doi:10.1080/23723556.2021.1973312

Hydrogen sulfide operates as a glioblastoma suppressor and is lost under high fat diet

Mol Cell Oncol. 2021 Sep 16;8(4):1973312. doi: 10.1080/23723556.2021.1973312. eCollection 2021.

Authors

Daniel J Silver^{1

2}, Justin D Lathia^{1

2

3

4}, Christopher Hine^{1

2

3}

Affiliations

¹ Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
² Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
³ Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁴ Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA.

Abstract

Glioblastoma (GBM) is one of the deadliest and aggressive forms of brain cancer. Environmental and intrinsic factors such as Western Diet and advanced age can function as powerful accelerants to the progression of GBM. Recently, we discovered that pre-clinical GBM models subject to an obesogenic and age-accelerating high fat diet (HFD) presented with hyperaggressive GBM phenotypes, including treatment-refractory cancer stem cell (CSC) enrichment. Mechanistically, HFD suppressed production of the gasotransmitter hydrogen sulfide (H₂S) and its downstream sulfhydration signaling in the brain. Likewise, we observed dramatic loss of sulfhydration in brains of GBM patients. Importantly, we showed the tumor suppressive effects of H₂S against GBM in cell culture and in vivo. Here, we discuss these recent findings and provide insight into how they can be leveraged to improve treatment modalities, prognosis, and quality of life for GBM patients.

Keywords: Glioblastoma (GBM); cancer stem cells (CSCS); cystathionine beta-synthase (CBS); cystathionine gamma-lyase (CGL); high fat diet (HFD); hydrogen sulfide (H2S); mercaptopyruvate sulfurtransferase (MPST); oleic acid (OA); sry transcription factor 2 (SOX2); sulfhydration; transsulfuration.

Grants and funding

Funding was provided by the Glioblastoma Research Organization (to CH), and pilot funding from the Case Comprehensive Cancer Center (to DJS, JDL, and CH).