Glycyl-tRNA Synthetase (GARS) Expression Is Associated with Prostate Cancer Progression and Its Inhibition Decreases Migration, and Invasion In Vitro

Abstract

Glycyl-tRNA synthetase (GARS) is a potential oncogene associated with poor overall survival in various cancers. However, its role in prostate cancer (PCa) has not been investigated. Protein expression of GARS was investigated in benign, incidental, advanced, and castrate-resistant PCa (CRPC) patient samples. We also investigated the role of GARS in vitro and validated GARS clinical outcomes and its underlying mechanism, utilizing The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Our data revealed a significant association between GARS protein expression and Gleason groups. Knockdown of GARS in PC3 cell lines attenuated cell migration and invasion and resulted in early apoptosis signs and cellular arrest in S phase. Bioinformatically, higher GARS expression was observed in TCGA PRAD cohort, and there was significant association with higher Gleason groups, pathological stage, and lymph nodes metastasis. High GARS expression was also significantly correlated with high-risk genomic aberrations such as PTEN, TP53, FXA1, IDH1, SPOP mutations, and ERG, ETV1, and ETV4 gene fusions. Gene Set Enrichment Analysis (GSEA) of GARS through the TCGA PRAD database provided evidence for upregulation of biological processes such as cellular proliferation. Our findings support the oncogenic role of GARS involved in cellular proliferation and poor clinical outcome and provide further evidence for its use as a potential biomarker in PCa.

Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology

“…It was also demonstrated that Fraisinib can inhibit the invasive ability of A549 cells. The pathogenetic role of GARS1 in oncology has recently been confirmed by a publication reporting that the silencing of GARS1 expression is effective in counteracting the progression of prostate cancer ( Khosh Kish et al, 2023 ). These data, together with the proven ability of this compound to cross the blood–brain barrier (BBB) ( Geretto et al, 2018 ), suggest that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases “in one shot.” Taken together, this work suggests that the inhibition of GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment.…”

Prognostic value of GARS in bladder cancer and its role in the tumor microenvironment

“…Importantly, Chen et al demonstrated that GARS is a reliable urinary biomarker in uroepithelial carcinoma ( 29 ). In prostate cancer cell lines, GARS knockdown reduces cell motility and invasion and causes S-phase cell arrest and early apoptotic signals ( 5 ). However, the biological function and biomarker role of GARS in BC have not been studied.…”

“…Khosh Kish et al demonstrated that GARS expression is associated with prostate cancer progression and its inhibition decreases migration, and invasion in vitro ( 5 ). Wang et al showed that GARS is implicated in poor survival and immune infiltration of hepatocellular carcinoma (HCC).…”

Exploration and review of the molecular mechanisms of hepatitis C virus infection-induced hepatocellular carcinoma

“…Including CHAC1, asparagine synthase (ASNS), PPP1R15A, TRIB3, these genes have been shown to play an important role in organ fibrosis or cancer progression. [37][38][39][40][41]. In HCV-infected liver cancer cells, there are significant changes in gene expression related to protein expression.…”