TGF-β-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK

Background: Cytokines of the transforming growth factor beta (TGF-beta) superfamily exert effects on proliferation, apoptosis and differentiation in various cell types. Cancer cells frequently acquire resistance to the anti-proliferative signals of TGF-beta, which can be due to mutations in proteins of the signalling cascade. We compared the TGF-beta-related signalling properties in B-cell lymphoma cell lines that were sensitive or resistant to TGF-beta-induced antiproliferative effects. Results: TGF-beta sensitive cell lines expressed higher cell surface levels of the activin receptor-like kinase 5 (Alk-5), a TGF-beta receptor type 1. The expression levels of the other TGF-beta and bone morphogenetic protein receptors were comparable in the different cell lines. TGF-beta-induced phosphorylation of Smad2 was similar in TGF-beta sensitive and resistant cell lines. In contrast, activation of Smad1/5 was restricted to cells that were sensitive to growth inhibition by TGF-beta. Moreover, with activin A we detected limited anti-proliferative effects, strong phosphorylation of Smad2, but no Smad1/5 phosphorylation. Up-regulation of the TGF-beta target genes Id1 and Pai-1 was identified in the TGF-beta sensitive cell lines. Constitutive phosphorylation of MAPK p38 was restricted to the TGF-b sensitive cell lines. Inhibition of p38 MAPK led to reduced sensitivity to TGF-beta. Conclusions: We suggest that phosphorylation of Smad1/5 is important for the anti-proliferative effects of TGF-beta in B-cell lymphoma. Alk-5 was highly expressed in the sensitive cell lines, and might be important for signalling through Smad1/5. Our results indicate a role for p38 MAPK in the regulation of TGF-beta-induced anti-proliferative effects.