Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Metformin is linked to reduced colorectal cancer (CRC) risk and better prognosis.
• The precise molecular mechanisms behind metformin's anti-CRC effects are not fully understood.

Purpose of the Study:

• To investigate metformin's activity in colorectal cancer models.
• To elucidate the molecular pathways through which metformin exerts its effects on CRC.

Main Methods:

• Cell cycle analysis (G1 arrest)
• Colony formation assays
• Luciferase assays
• Protein synthesis and proteasome inhibition studies
• Polysome profiling
• Ribopuromycylation assays
• Analysis of mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling pathways.

Main Results:

• Metformin inhibits CRC cell proliferation and colony formation by inducing G1 cell cycle arrest.
• Metformin significantly reduces MYC protein levels.
• The reduction in MYC is mediated by inhibiting protein synthesis, not proteasomal degradation or 3' UTR regulation.
• Metformin broadly suppresses protein synthesis, particularly affecting cell cycle-associated proteins via mTOR and MNK1 signaling axes.

Conclusions:

• Metformin's inhibition of colorectal cancer cell proliferation is linked to reduced MYC protein synthesis.
• The suppression of protein synthesis, especially for cell cycle proteins, is a key mechanism of metformin's anti-cancer activity.
• Targeting MYC protein synthesis may be a therapeutic strategy for colorectal cancer.