mTORC2 promotes cell survival through c-Myc-dependent up-regulation of E2F1

Area of Science:

• Cell Biology
• Molecular Oncology
• Cancer Research

Background:

• The mechanistic target of rapamycin complex 2 (mTORC2) is known to promote cell survival by phosphorylating AKT.
• The precise mechanisms by which mTORC2 regulates apoptosis remain incompletely understood.

Purpose of the Study:

• To elucidate a novel mechanism by which mTORC2 controls apoptosis.
• To investigate the role of mTORC2 in regulating c-Myc, miR-9-3p, and E2F1 expression in cancer cells.

Main Methods:

• Utilized in vitro cell culture and in vivo mouse models, including B cell-specific mTORC2 deletion mice and xenograft tumor models.
• Assessed protein and gene expression levels, including c-Myc, miR-9-3p, and E2F1.
• Employed Antagomir-9-3p to investigate the role of miR-9-3p in vivo.

Main Results:

• Inactivation of mTORC2 led to increased binding of CIP2A to PP2A, reduced PP2A activity, and subsequent enhancement of c-Myc phosphorylation and expression.
• Elevated c-Myc activity induced miR-9-3p transcription, which inhibited E2F1 expression, resulting in enhanced apoptosis.
• In vivo studies confirmed that mTORC2 inactivation up-regulated c-Myc and miR-9-3p, down-regulated E2F1, and reduced cell survival.

Conclusions:

• mTORC2 promotes cancer cell survival by stimulating E2F1 expression through a c-Myc- and miR-9-3p-dependent pathway.
• Targeting the mTORC2/c-Myc/miR-9-3p/E2F1 axis represents a potential therapeutic strategy for enhancing apoptosis in cancer.