Protocatechuic acid promotes c-Myc-mediated cell proliferation by directly targeting TRAF2

Area of Science:

• Molecular Biology
• Cellular Signaling
• Pharmacology

Background:

• Protocatechuic acid (PCA), a plant-derived phenolic acid and gut metabolite, has shown cytotoxic effects in vitro at high concentrations.
• Dietary intake results in non-toxic nano- to micromolar plasma levels of PCA, suggesting context-dependent biological activity.
• The molecular targets and mechanisms underlying PCA's physiological effects at relevant concentrations remain largely unexplored.

Purpose of the Study:

• To identify direct molecular targets of protocatechuic acid (PCA) at physiologically relevant concentrations.
• To elucidate the mechanism by which PCA influences cell viability.
• To investigate the role of the adaptor protein TNF Receptor Associated Factor 2 (TRAF2) in PCA's cellular effects.

Main Methods:

• Computational modeling and biophysical assays (fluorescence spectroscopy, calorimetry) to assess PCA-TRAF2 interaction.
• Functional analyses in HAP1 leukemia cells to evaluate PCA's impact on cell viability.
• Investigation of downstream signaling pathways (JNK, c-Myc) affected by PCA-TRAF2 interaction.

Main Results:

• PCA directly binds to the TRAF domain of TRAF2, reducing its thermal stability and potentially altering its trimeric structure.
• At low micromolar concentrations, PCA significantly increases cell viability in a TRAF2-dependent manner.
• PCA binding to TRAF2 inhibits JNK signaling and promotes pro-survival signaling via c-Myc.

Conclusions:

• TNF Receptor Associated Factor 2 (TRAF2) is identified as a novel direct molecular target of protocatechuic acid (PCA).
• PCA enhances cell viability through a TRAF2-dependent mechanism involving modulation of JNK and c-Myc signaling.
• These findings provide a mechanistic understanding of PCA's beneficial effects at non-toxic, physiologically relevant concentrations.