TGFβ modulates PTEN expression independently of SMAD signaling for growth proliferation in colon cancer cells

Abstract

Signaling pathways enabling transforming growth factor-b (TGFb)'s conversion from a tumor suppressor to a tumor promoter are not well characterized. TGFb utilizes intracellular SMADs to mediate growth suppression; however, TGFb-induced proliferative pathways may become more apparent when SMAD signaling is abrogated. Here, we determined regulation of the tumor suppressor PTEN by TGFb utilizing SMAD4-null colon cancer cells. TGFb downregulated PTEN mRNA and simultaneously induced growth proliferation. TGFb 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 TGFb-induced cell proliferation, but downregulation of PTEN expression by TGFb was unaffected. TGFb increased PI3K tyrosine phosphorylation, and inhibition of PI3K pharmacologically or by DN-p85 transfection reversed both TGFb-induced PTEN suppression and TGFb-induced cell proliferation. Thus, TGFb activates PI3K to downregulate PTEN for enhancement of cell proliferation that is independent of SMAD proteins.

Signaling via Alk5 controls the ontogeny of lung Clara cells

“…A number of observations support the validity of this hypothetical model. First, TGFb modulation of Pten, as the effect of TGFb on Hes1 occurs independently of Smad signaling (Chow et al, 2008). Second, and as we found in this study (Fig.…”

“…Deletions and mutations in the Pten gene have been associated with multiple forms of human cancers (Steck et al, 1997). Both in vivo and in vitro results showed that Pten is negatively regulated by TGFb (Kattla et al, 2008;Chow et al, 2008). In glioblastomas, MEK/ERK activity is downregulated by PTEN through inhibition of SHC phosphorylation (Gu et al, 1998).…”

“…Pten is also negatively regulated by TGFb1 via Smadindependent signaling (Chow et al, 2008). In similar experiments to those described above, we used MLE15 cells and assayed for expression of a number of genes in the presence and absence of TGFb1 and SB-52334, an ALK5-specific inhibitor.…”

The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia

“…23,33 In future, the level of SMAD-4 protein could possibly become a marker for monitoring disease activity in patients with pancreatic cancer. Interestingly, similar observations apply to patients with gastrointestinal tract tumors, including stomach 20,34 and colorectal tumors 19,35,36 as well as ovarian cancer. 37 In addition to numerous reports of decreased SMAD-4 expression in solid tumors, studies were also carried out in patients with hematologic malignancies.…”

“…[17][18][19] The most common mutation is being that of the SMAD-4 protein, which is observed in 50% of patients with pancreatic cancer, 20% with colon cancer, and 10% with lung cancer. [20][21][22][23][24] Similar mutations have been observed in patients with hematological malignancies, including acute myeloid leukemia (AML). 25 Moreover, a low or undetectable level of SMAD-4 was related to tumor progression, metastasis, and unfavorable prognosis in many different types of cancer.…”