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Exp Cell Res. 2007 Sep 10;313(15):3167-74. Epub 2007 Jun 29.

Smad4-independent, PP2A-dependent apoptotic effect of exogenous transforming growth factor beta 1 in lymphoma cells.

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  • 1Semmelweis University, I. Department of Pathology and Experimental Cancer Research, 1085 Budapest, Ulloi út 26, Hungary. anna@korb1.sote.hu

Abstract

B-lymphoid tumor cells are often less sensitive than their normal counterparts or insensitive to transforming growth factor beta1 (TGFb) effects. We studied the apoptotic effect of exogenous TGFb in B-lymphoma cells, focusing on the activity and the role of Smad and protein phosphatase/kinase signals. Recombinant TGFb treatment and Smad4 siRNA transfection were used in HT58 B-NHL lymphoma cells in vitro. Gene expression and apoptosis were detected by RT-PCR, Western blot analysis and flow cytometry. The role of MEK1 kinase and PP2A activity--measured with a phosphatase assay--were assessed with the help of specific inhibitors. Smad4 siRNA treatment completely abolished TGFb-induced early gene upregulation, indicating the absence of the rapid activation of Smad signaling. Moreover, functional inhibition of Smad4 had no influence on TGFb-induced apoptosis, but it was dependent on PP2A phosphatase activation, ERK1/2 and JNK inactivation in lymphoma cells. The results prove that exogenous TGFb uses Smad4-independent, alternative (PP2A/PP2A-like dependent) signaling pathways for apoptosis induction in lymphoma cells. Further studies are needed to clarify the possible role and involvement of Smad4-independent effects of TGFb in normal and malignant lymphoid cells and in cells of the tumor microenvironment.

PMID:
17643425
DOI:
10.1016/j.yexcr.2007.05.028
[PubMed - indexed for MEDLINE]
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