Activation of cAMP-responsive-element-binding protein by PI3 kinase and p38 MAPK is essential for elevated expression of transforming growth factor ß2 in cancer cells.

Transforming growth factor ß2 (TGFß2) is highly expressed in a variety of different cancer cell lines. Using Z12 cells, a mutant of 293 cells with overexpression of TGFß2, we found that the cyclic adenosine monophosphate (cAMP)-responsive element (CRE) sequence in the promoter of the TGFß2 gene is crucial for its increased expression. Further, constitutive phosphorylation of CRE-binding protein (CREB) is increased in these cells. Treating Z12 cells with either the PI3 kinase inhibitor LY294002 or the p38 MAPK inhibitor SB203580 significantly inhibited both the phosphorylation of CREB and expression of TGFß2. In addition, treating Z12 or cancer cell lines with either of these 2 inhibitors significantly decreased their secretion of TGFß2. These data suggest that activated PI3 kinase and p38 MAPK play important roles in high expression of TGFß2 in cancer cells by stimulating the phosphorylation of CREB, which activates the CRE in the promoter of the TGFß2 gene. We have identified an important link between PI3 kinase, p38 MAPK, and TGFß2, providing an additional rationale for using inhibitors of these kinases as therapeutic drugs in cancer.