Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.

In normal epithelial tissues, the multifunctional cytokine transforming growth factor-beta (TGF-beta) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-beta promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-beta shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-beta. The TGF-beta effector SMAD3 inducibly interacts with PTEN on TGF-beta treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-beta-mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-beta-regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-beta-mediated invasion but does not affect TGF-beta-mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-beta-induced invasion but does not modulate TGF-beta-mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-beta receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-beta-mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-beta as a tumor enhancer with specific effects on cellular motility and invasion.

[1]  Fang Liu,et al.  Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. , 2005, Biochemistry.

[2]  Fang Liu,et al.  Cyclin-dependent kinases regulate the antiproliferative function of Smads , 2004, Nature.

[3]  D. Bigner,et al.  SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility. , 2004, Molecular cancer therapeutics.

[4]  S. Anderson,et al.  Integration of Smad and Forkhead Pathways in the Control of Neuroepithelial and Glioblastoma Cell Proliferation , 2004, Cell.

[5]  K. Luo,et al.  Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis , 2004, Nature Cell Biology.

[6]  Stephen W. Michnick,et al.  PKB/Akt modulates TGF-β signalling through a direct interaction with Smad3 , 2004, Nature Cell Biology.

[7]  Yigong Shi,et al.  Transforming Growth Factor (cid:2) -Mediated Transcriptional Repression of c- myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element , 2022 .

[8]  P. Andreasen,et al.  Plasminogen activator inhibitor-1 and tumour growth, invasion, and metastasis , 2004, Thrombosis and Haemostasis.

[9]  J. Massagué,et al.  Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer , 2003, Nature Reviews Cancer.

[10]  J. Massagué,et al.  Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus , 2003, Cell.

[11]  Jacqueline Palmari,et al.  PAI-1 and EGFR expression in adult glioma tumors: toward a molecular prognostic classification. , 2002, International journal of radiation oncology, biology, physics.

[12]  William R. Sellers,et al.  Phosphorylation of the PTEN Tail Acts as an Inhibitory Switch by Preventing Its Recruitment into a Protein Complex* , 2001, The Journal of Biological Chemistry.

[13]  Tomohiko Maehama,et al.  Crystal Structure of the PTEN Tumor Suppressor Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association , 1999, Cell.

[14]  H. Hanafusa,et al.  The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Wigler,et al.  The lipid phosphatase activity of PTEN is critical for its tumor supressor function. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Gordon Mills,et al.  Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC , 1998, Current Biology.

[17]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[18]  Xiao-Fan Wang,et al.  Functional Analysis of the Transforming Growth Factor βResponsive Elements in the WAF1/Cip1/p21 Promoter (*) , 1995, The Journal of Biological Chemistry.

[19]  J. Billadello,et al.  Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. , 1991, The Journal of biological chemistry.