GLUD1 suppresses renal tumorigenesis and development via inhibiting PI3K/Akt/mTOR pathway

Abstract

Growing cancer cells are addicted to glutamine. Glutamate dehydrogenase 1 (GLUD1) is one of key enzymes in glutamine metabolism and plays a critical role in the malignancy of diverse tumors. However, its role and molecular mechanism in clear cell renal cell carcinoma (ccRCC) development and progression remain unknown. In this study, analysis results of the GEO/TCGA/UALCAN database showed that GLUD1 level was downregulated in ccRCC tissues. Immunohistochemistry and western blotting results further validated the downregulation of GLUD1 level in ccRCC tissues. GLUD1 level was gradually decreased as ccRCC stage and grade progressed. Low GLUD1 level was associated with a shorter survival and higher IC50 value for tyrosine kinase inhibitors (TKIs) in ccRCC, reminding that GLUD1 level could predict the prognosis and TKIs sensitivity of ccRCC patients. High level of methylation in GLUD1 promoter was positively correlated with the downregulation of GLUD1 level and was negatively correlated with survival of ccRCC patients. GLUD1 overexpression suppressed RCC cell proliferation, colony formation and migration by inhibiting PI3K/Akt/mTOR pathway activation. Low GLUD1 level correlated with suppressive immune microenvironment (TIME) in ccRCC. Together, we found a novel tumor-suppressing role of GLUD1 in ccRCC which was different from that in other tumors and a new mechanism for inhibiting PI3K/Akt/mTOR activation and TIME in ccRCC. These results provide a theoretical basis for GLUD1 as a therapeutic target and prognostic marker in ccRCC.

LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway

“…Previous research has shown that M2-EV inhibits NEDD4L through the transmission of miR-342-3p, thereby suppressing the ubiquitination and degradation of CEP55 by activating the PI3K/AKT/mTOR signaling pathway, which in turn promotes RCC cell growth, migration, and invasion [ 66 ]. Furthermore, viaGLUD1 inhibits kidney tumor occurrence and development by suppressing the PI3K/Akt/mTOR pathway [ 67 ], while LINC00460 promotes RCC development by affecting the PI3K/AKT pathway and decreasing the phosphorylation levels of AKT and mTOR [ 68 ].…”

Biochemical and clinical effects of RPS20 expression in renal clear cell carcinoma

“…AKT signaling is additionally engaged in numerous biological processes, including glucose metabolism and cell cycle, particularly in cancer cells ( 50 ). AKT signaling is suppressed in ccRCC cells, which reduces invasion and metastasis ( 51 ). In the present study, it was demonstrated that RPS20 knockdown suppresses MAPK and AKT signaling in ccRCC.…”

Glutamine metabolism in tumor metastasis: Genes, mechanisms and the therapeutic targets

“…In addition, GLUD1 level is negatively associated with immunosuppressive microenvironment in ccRCC. These results suggest a negative correlation between GDH and adverse outcomes such as metastasis in ccRCC [ 61 ].…”