Englander Institute for Precision Medicine

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.

TitleCysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
Publication TypeJournal Article
Year of Publication2024
AuthorsNoch EK, Palma L, Yim I, Bullen N, Barnett D, Walsh A, Bhinder B, Benedetti E, Krumsiek J, Gurvitch J, Khwaja S, Atlas D, Elemento O, Cantley LC
JournalProc Natl Acad Sci U S A
Date Published2024 Feb 20
KeywordsAcetylcysteine, Animals, Brain Neoplasms, Cell Line, Tumor, Glioblastoma, Glucose, Humans, Hydrogen Peroxide, Mice, Peroxides, Proteomics

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID38359293
PubMed Central IDPMC10895255
Grant ListR35 CA197588 / CA / NCI NIH HHS / United States
S10 RR027699 / RR / NCRR NIH HHS / United States

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