Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Aberrant activation of the mechanistic target of rapamycin (mTOR) pathway, driven by genetic alterations, is a key factor in cancer development.
• The specific downstream molecules regulated by mTOR that contribute to tumorigenesis are not fully understood.

Purpose of the Study:

• To identify novel downstream effectors of the mTOR pathway.
• To investigate the role of brain-expressed X-linked 2 (BEX2) in mTOR-driven tumorigenesis.
• To elucidate the signaling pathway linking mTOR to tumor growth.

Main Methods:

• Utilized genetically modified mouse models (Tsc2(-/-), Pten(-/-), Tsc1 knock-out, Tsc2 heterozygous deletion) and cell lines.
• Administered the mTOR inhibitor rapamycin to assess BEX2 regulation.
• Investigated the involvement of STAT3 and NF-κB signaling pathways.
• Assessed the impact of BEX2 depletion on tumor growth and vascular endothelial growth factor (VEGF) production.

Main Results:

• Identified brain-expressed X-linked 2 (BEX2) as a novel downstream target of mTOR.
• Elevated BEX2 levels in various cancer models and a patient with tuberous sclerosis complex (TSC) were reversed by rapamycin treatment.
• mTOR-mediated upregulation of BEX2 occurs through parallel activation of STAT3 and NF-κB.
• BEX2 promotes VEGF production and angiogenesis, contributing to tumor growth.
• Depletion of BEX2 inhibited tumorigenesis in cells with hyperactive mTOR.

Conclusions:

• The STAT3/NF-κB-BEX2-VEGF signaling axis is a critical pathway in mTOR-driven tumorigenesis.
• BEX2 is a key mediator of mTOR's pro-tumorigenic effects.
• Targeting BEX2 presents a potential therapeutic strategy for cancers with activated mTOR signaling.