Integrated proteomic and metabolomic profiling the global response of rat glioma model by temozolomide treatment.

Abstract

Temozolomide (TMZ) is the first-line chemotherapeutic drug for glioblastoma treatment. It can induce O6-methylguanine DNA lesions, lead to prolonged G2-M arrest and ultimately cell death. However, the molecular response induced by TMZ has not been fully elucidated. In this study, by integrating quantitative proteomics and metabolomics, we identified protein and metabolite markers that correlate with TMZ treatment and discovered the protein-metabolite regulatory network. A total of 1782 proteins and 56 endogenous metabolites were significantly altered in the brain between sham and tumor groups, 38 metabolites markedly altered in plasma. After TMZ treatment, 251 proteins and 9 metabolites significantly changed in the brain, and 14 metabolites did in plasma. 35 proteins significantly altered by TMZ were further validated by parallel reaction monitoring (PRM) analysis. The multi-omics analysis revealed differential proteins and metabolites were involved in DNA replication, nucleotides degradation, cysteine biosynthesis, and other pathways. Adenosine, sarcosine and adenosine deaminase involved in multiple metabolic pathways may serve as potential biomarkers for TMZ treatment. This is the first report utilizing multi-omics analysis to investigate the global response of proteins and metabolites in glioma by TMZ treatment, and the data can provide a comprehensive insight to understand the mechanism of TMZ. SIGNIFICANCE: The study focused on integrating quantitative proteomics and endogenous metabolites profiling of the rat glioma brain in response to chemotherapeutic drug temozolomide treatment, which has not yet been reported. The results showed that the effect of temozolomide on glioma is significant, including DNA replication, nucleotides degradation, cysteine biosynthesis, and synaptogenesis signaling pathway. Our study can provide a comprehensive insight to screen potential targets and biomarkers of glioma as well as to elucidate the mechanism of temozolomide inhibiting tumor growth.