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

Lei Wang1, Zhiyu Fang2, Peixiang Gao2

  • 1Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Frontiers in Oncology
|October 7, 2022
PubMed

Insights

Glutamate dehydrogenase 1 (GLUD1) suppresses clear cell renal cell carcinoma (ccRCC) by inhibiting PI3K/Akt/mTOR signaling and improving the tumor immune microenvironment. Lower GLUD1 levels predict poor prognosis and reduced sensitivity to tyrosine kinase inhibitors in ccRCC patients.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer biology

Background:

  • Glutamine metabolism is crucial for cancer cell growth.
  • Glutamate dehydrogenase 1 (GLUD1) is a key enzyme in glutamine metabolism with varied roles in different cancers.
  • The function of GLUD1 in clear cell renal cell carcinoma (ccRCC) is not well understood.

Purpose of the Study:

  • To investigate the role and molecular mechanism of GLUD1 in ccRCC development and progression.
  • To determine if GLUD1 can serve as a prognostic marker or predict treatment sensitivity in ccRCC.

Main Methods:

  • Bioinformatic analysis of GEO, TCGA, and UALCAN databases.
  • Immunohistochemistry and western blotting to validate GLUD1 expression.
  • Correlation analysis of GLUD1 levels with clinical stage, grade, survival, and methylation.
  • Investigation of GLUD1's effect on cell proliferation, migration, and signaling pathways (PI3K/Akt/mTOR).
  • Assessment of GLUD1's impact on the tumor immune microenvironment (TIME).

Main Results:

  • GLUD1 was significantly downregulated in ccRCC tissues, with levels decreasing as stage and grade increased.
  • Low GLUD1 expression correlated with shorter patient survival and higher resistance to tyrosine kinase inhibitors (TKIs).
  • Increased promoter methylation of GLUD1 was associated with reduced GLUD1 levels and poorer survival.
  • Overexpression of GLUD1 inhibited ccRCC cell proliferation, colony formation, and migration by suppressing the PI3K/Akt/mTOR pathway.
  • Low GLUD1 levels were linked to a suppressive tumor immune microenvironment in ccRCC.

Conclusions:

  • GLUD1 acts as a tumor suppressor in ccRCC, a role distinct from its function in other cancers.
  • GLUD1 inhibits ccRCC progression by modulating the PI3K/Akt/mTOR pathway and influencing the tumor immune microenvironment.
  • GLUD1 represents a potential therapeutic target and prognostic biomarker for ccRCC, predicting patient outcomes and TKI sensitivity.
Keywords:
GLUD1PI3K/Akt/mTORmethylationprognosisrenal cell carcinoma

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