A mechanistic study of the proapoptotic effect of tolfenamic acid: involvement of NF-κB activation

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• Tolfenamic acid (TA) shows anti-cancer properties by inducing apoptosis, but its precise mechanisms, especially concerning the nuclear factor-kappaB (NF-κB) pathway in colorectal cancer, require further investigation.
• The NF-κB signaling pathway is crucial in inflammation and cancer progression, and non-steroidal anti-inflammatory drugs can modulate it, yet its specific interaction with TA-induced apoptosis in colorectal cancer remains unclear.

Purpose of the Study:

• To investigate the effects of tolfenamic acid (TA) on the NF-κB signaling pathway and apoptosis in human colorectal cancer cells.
• To elucidate the molecular mechanisms underlying TA-induced apoptosis, focusing on the interplay between NF-κB, p53, and specific kinase pathways.

Main Methods:

• Assessed TA's impact on NF-κB transcriptional activity and DNA binding.
• Investigated IκB-α phosphorylation and degradation, p65 nuclear translocation, and p65 phosphorylation at Ser276.
• Utilized p53 knockout and p65 point mutation models to analyze TA's effects on NF-κB and apoptosis.

Main Results:

• TA activated NF-κB transcriptional activity and DNA binding via increased IκB-α phosphorylation and degradation, leading to p65 nuclear translocation.
• TA enhanced p65 nuclear accumulation and stability through increased phosphorylation at Ser276, mediated by p38 MAPK and ERK.
• TA-induced apoptosis was dependent on both NF-κB (p65) and p53, with TA also enhancing p53 transcriptional activity and p53-p65 binding.

Conclusions:

• Tolfenamic acid induces apoptosis in colorectal cancer cells through a novel mechanism involving the activation of the NF-κB pathway and p53.
• TA's effects are mediated by p38 MAPK and ERK pathways, leading to p65 phosphorylation and subsequent activation of both NF-κB and p53 transcriptional activities.