RagC and Map4K3 deficiency in high-grade gliomas drives proliferation and modulates mTORC1-dependent cellular...

Area of Science:

• Cellular Biology
• Oncology
• Molecular Signaling

Background:

• Cellular growth and homeostasis rely on amino acid-sensing pathways, primarily mediated by the mTOR signaling pathway.
• Rag GTPases and Map4K3 act as critical amino acid sensors, modulating mTOR signaling.
• Dysregulated mTOR signaling in relation to amino acid sensors may influence astrocytic tumor proliferation and treatment outcomes.

Purpose of the Study:

• To investigate the role of RagC and Map4K3 in astrocytic tumors.
• To determine the impact of RagC and Map4K3 deficiency on glioma cell proliferation, morphology, motility, and underlying mTOR signaling mechanisms.

Main Methods:

• Studied RagC and Map4K3 expression in human gliomas and various cell lines.
• Generated RagC and Map4K3 knockout glioma cells using CRISPR-Cas and shRNA techniques.
• Analyzed proliferation, morphology, motility, mTOR signaling pathway components (p70S6K, RagD, TFEB), autophagy, and senescence in deficient cells under varying amino acid conditions.

Main Results:

• High-grade astrocytomas exhibited significantly reduced RagC and Map4K3 immunoreactivity compared to low-grade astrocytomas.
• RagC- and Map4K3-deficient glioma cells displayed increased proliferation, altered morphology, and motility.
• Map4K3 deficiency reduced proliferation under leucine deprivation, while RagC deficiency led to increased senescence and no autophagy induction; RagC/Map4K3 deficiency altered mTOR signaling (p70S6K phosphorylation, RagD, TFEB expression).

Conclusions:

• Loss of RagC and Map4K3 in malignant gliomas promotes proliferation.
• RagC and Map4K3 deficiencies differentially impact mTOR signaling, autophagy, and senescence.
• These findings highlight the role of RagC and Map4K3 as potential modulators of astrocytic tumor progression.