Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting...

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Cancer development involves translatome dysregulation, with aberrant mRNA elongation and eukaryotic initiation factor 5A (eIF5A) expression contributing to tumor growth.
• Targeting translation factors presents potential therapeutic strategies for neoplasms.

Purpose of the Study:

• To investigate the efficacy of targeting eIF5A with the inhibitor GC7 as a strategy to inhibit aberrant cancer cell growth.
• To elucidate the molecular mechanisms by which eIF5A inhibition affects protein synthesis and cancer cell proliferation.

Main Methods:

• Utilized the eIF5A inhibitor GC7 to study its effects on cancer cell growth.
• Employed dynamic SILAC (Stable Isotope Labeling by Amino acids in Cell culture) to identify proteins affected by reduced eIF5A activity.
• Investigated the role of integrated stress response (ISR) and mitochondrial function in mediating the effects of GC7.

Main Results:

• Inhibiting eIF5A activity with GC7 induced feedback inhibition of translation initiation via eIF2α phosphorylation, leading to reduced protein synthesis.
• Decreased eIF5A activity impaired mitochondrial function, activating HRI signaling to eIF2α phosphorylation and subsequently reducing cancer cell proliferation.
• The observed effects of GC7 on cancer cell proliferation were reversed by an integrated stress response inhibitor, indicating mediation via translation initiation.

Conclusions:

• eIF5A inhibition by GC7 effectively curtails aberrant cancer cell growth by disrupting protein synthesis and mitochondrial function.
• The anti-cancer effects of GC7 are primarily mediated through the integrated stress response and feedback inhibition of translation initiation.
• Targeting eIF5A represents a potential therapeutic strategy for cancers reliant on mitochondrial function for proliferation and survival.