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Tired of looking for an online movie title, or not knowing which video player to use.^[@R10]^ and may represent a novel therapeutic target. The common molecular pathway for TGFβ-induced cancer cell migration is activation of MAPK, which is downstream of multiple cellular-signaling pathways. Although there are many distinct TGFβ receptors, TβRI appears to be the primary mediator of TGFβ signaling and has been linked to TGFβ–induced EMT and pericellular proteolytic remodeling in various types of cancer.^[@R11]–[@R14]^ Our results suggest that the interference with TβRI/Smad2/3 signaling may be an option to counteract cancer cell migration, invasion, and metastasis.
The present study indicates that TβRI signaling is essential for TGFβ2–induced cancer cell migration. TβRI inhibition by metenolone or SB431542 prevents cell migration in various cell lines, without interfering with cell viability, cell proliferation, or cell cycle progression. We found that TβRI inhibition was effective to prevent cancer cell migration and TGFβ2-induced α-SMA expression. It is possible that TGFβ2 may induce Smad2/3 by a TβRI-independent pathway, but this is unlikely. We observed a Smad2/3-independent TGFβ2-induced Smad4 phosphorylation (at S467), which was inhibited by metenolone or SB431542 treatment. There was also significant reduction of p-Smad3 in cell lines with Smad2/3 knockdown. These results suggest that metenolone and SB431542 may inhibit TGFβ-induced cancer cell migration in an Smad2/3-independent manner. However, we cannot completely rule out this possibility because the effects of metenolone and SB431542 on Smad4 phosphorylation (at S467) and p-Smad3 were blocked by Smad4 knockdown. Furthermore, we performed experiments with Smad3 knockdown to support this hypothesis. However, we have no data on Smad3 knockdown because no siRNA targeting human Smad3 has been commercially available.
We are also interested in knowing whether the TβRI inhibitor can be effective for other types of cancer cells. In addition to tumor cells, we have confirmed that metenolone and SB431542
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