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

Transforming growth factor-beta (TGF-beta) modulates diverse cell physiological processes and plays a complicated role in tumor development. It has been well established that TGF-beta inhibits cell proliferation in normal and early stage carcinoma and facilitates tumor metastasis in late-stage carcinoma. Therefore, blocking TGF-beta signaling in advanced stage carcinogenesis provides a potentially interesting chemotherapeutic strategy. We aimed to determine the effect of tolfenamic acid (TA) on TGF-beta-induced protumorigenic activity. Here, we demonstrate that TA attenuates tumor-promoting effects of TGF-beta in cancer cells. Further observation indicates TA blocks the TGF-beta/Smad pathway, and this blockage is mainly attributed to the interference of TGF-beta 1-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-beta 1-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-beta 1. Our study provides a possible mechanism by which TA affects anticancer activity by inhibiting the TGF-beta pathway and sheds light on the application of TA for cancer patients.