Abstract
Signaling pathways enabling transforming growth factor-beta (TGFβ)’s conversion from a tumor suppressor to a tumor promoter are not well characterized. TGFβ utilizes intracellular SMADs to mediate growth suppression; however, TGFβ-induced proliferative pathways may become more apparent when SMAD signaling is abrogated. Here, we determined regulation of the tumor suppressor PTEN by TGFβ utilizing SMAD4-null colon cancer cells. TGFβ downregulated PTEN mRNA and simultaneously induced growth proliferation. TGFβ also induced both SMAD2 and SMAD3 nuclear translocation, but only triggered SMAD2-specific transcriptional activity in the absence of SMAD4. Interference of SMAD2 with DN-SMAD2 enhanced TGFβ-induced cell proliferation, but downregulation of PTEN expression by TGFβ was unaffected. TGFβ increased PI3K tyrosine phosphorylation, and inhibition of PI3K pharmacologically or by DN-p85 transfection reversed both TGFβ-induced PTEN suppression and TGFβ-induced cell proliferation. Thus, TGFβ activates PI3K to downregulate PTEN for enhancement of cell proliferation that is independent of SMAD proteins.
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