Disruption of the transforming growth factor-ß pathway by tolfenamic acid via the ERK MAP kinase pathway.

ABSTRACT

Transforming growth factor-ß (TGF-ß) modulates diverse cell physiological processes and plays a complicated role in tumor development. It has been well established that TGF-ß inhibits cell proliferation in normal and early stage carcinoma and facilitates tumor metastasis in late-stage carcinoma. Therefore, blocking TGF-ß signaling in advanced stage carcinogenesis provides a potentially interesting chemotherapeutic strategy. We aimed to determine the effect of tolfenamic acid (TA) on TGF-ß-induced protumorigenic activity. Here, we demonstrate that TA attenuates tumor-promoting effects of TGF-ß in cancer cells. Further observation indicates TA blocks the TGF-ß/Smad pathway, and this blockage is mainly attributed to the interference of TGF-ß1-driven phosphorylation of Smad2/3. We also show that TA could exert this effect on cancer cell lines from several different origins and that TA is much better than other non-steroidal anti-inflammatory drugs with respect to inhibition of TGF-ß1-induced Smad2 phosphorylation. Finally, extracellular signal-regulated kinase mitogen-activated protein kinase plays a role in TA-induced suppression of Smad2/3 phosphorylation and subsequent nuclear accumulation of Smad2/3 in response to TGF-ß1. Our study provides a possible mechanism by which TA affects anticancer activity by inhibiting the TGF-ß pathway and sheds light on the application of TA for cancer patients.