Targeting the transforming growth factor-β signaling pathway in human cancer

Nagaraj, Nagathihalli S.; Datta, Pran K.

doi:10.1517/13543780903382609

Cited by 245 publications

(196 citation statements)

References 107 publications

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“…During the early stages of carcinogenesis, TGF-β1 exhibits a predominantly inhibitory effect on growth, and serves as a tumor suppressor. However, with the development of malignancy, TGF-β1 promotes tumor cell invasion and metastasis (8,9). Previous studies have demonstrated that high expression levels of TGF-β1 have a close association with gastric cancer (10), lung cancer (11), colon cancer (10,12) and other malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Ding

Cui

et al. 2016

Oncology Letters

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Abstract. The aim of the present study was to investigate the association between the expression levels of transforming growth factor-β1 (TGF-β1) and the clinical pathological characteristics and prognosis of triple negative breast cancer (TNBC) through study of TNBC patient tissue samples. The biological effects of TGF-β1 on TNBC cells and the potential signal transduction pathway are additoinally investigated. Immunohistochemistry was utilized to investigate expression changes of the positive rate of TGF-β1 in the TNBC, compared with the non-TNBC group, to explain the association between TGF-β1 and clinical pathological characteristics and prognosis. MDA-MB-231 cells were treated with TGF-β1 and subsequently the invasion and migration abilities, and the expression of proteins in certain signaling pathways were assessed before and after the treatment. Positive expression of TGF-β1 was observed in 52.5% of TNBC tissue samples, which was higher than that observed in non-TNBC group (27.5%). High levels of TGF-β1 expression were not significantly associated age, menopausal status, family history of cancer or tumor size; however, tumor histological grade and axillary lymph node metastasis were significantly associated (P<0.05). In addition, when the TGF-β1 expression levels are higher, the 5-year disease-free survival rate is lower. TGF-β1 expression promoted the invasion and migration of MDA-MB-231 cells, and the expression of Smad2 protein and P38 protein was increased, indicating that Smad2 protein and the P38 signaling pathway may serve an important role in TNBC.

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Section: Discussionmentioning

confidence: 99%

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Ding

Cui

et al. 2016

Oncology Letters

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“…Here, we also found that phosphorylation of CdGAP was transiently increased in response to TGFb stimulation of NMuMG cells, following the same kinetic observed for TGFbinduced Smad2/3 phosphorylation. It will be of great interest to determine whether CdGAP is a direct phosphorylation substrate of type I/II receptors or is targeted by non-smad pathways activated by TGFb (Nagaraj and Datta, 2010). Interestingly, a study using the automated high-throughput technology LUMIER (luminescence-based mammalian interactome mapping) to map protein-protein interaction networks in the TGFb signaling pathway in mammalian cells identified CdGAP as a protein interactor in the TGFb signaling network .…”

Section: Discussionmentioning

confidence: 99%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPaseactivating protein (CdGAP) is a serine-and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signalregulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-b (TGFb) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFb to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFb-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFb-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFb. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFbinduced cell motility and invasion. Finally, we found that TGFb induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFb signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFb and Neu/ErbB-2 signaling pathways in breast cancer cells.

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“…Transforming growth factor-β (TGF-β) is a multifunctional cytokine and plays very important roles in development, differentiation and in maintaining homeostasis in almost all cell types and tissues (1). TGF-β functions via transmembrane serine/threonine kinase receptors, the type I and type II receptors (TGF-βRI and TGF-βRII) (2) and intracellular Smad transcriptional regulators (3).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

et al. 2012

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Abstract.Recent studies have shown that transforming growth factor-β1 (TGF-β1) signaling plays important roles in the redox system in benign and malignant cells. Whether TGF-β mediates an antioxidative damage response in colorectal cancer cells is largely unknown. Herein, using the human colorectal cancer cell lines we found that TGF-β1 induced glutathione peroxidase-1 (GPx-1) expression and enzyme activity, and that the upregulation of GPx-1 by TGF-β1 could protect colorectal cell lines from H 2 O 2 -induced oxidation damage. Further, we used loss-and gain-function approaches to elucidate the underlying mechanism and found that TGF-β1 induced GPx-1 through activation of the TGF-β receptor type I (TGF-βRI)/ Smad2/extracellular-signal-regulated kinase 1/2 (ERK1/2)/ hypoxia-inducible factor-1α (HIF-1α) signaling pathway. This cascade could be blocked by the TGF-βRI inhibitor or ERK1/2 inhibitor. Taken together, our data demonstrated that TGF-β1 induced GPx-1 expression and enzymatic activity via the TGF-βRI/Smad2/ERK1/2/HIF-1α signaling pathway, suggesting a novel antioxidative protective function of TGF-β1 in colorectal cancer cells. IntroductionTransforming growth factor-β (TGF-β) is a multifunctional cytokine and plays very important roles in development, differentiation and in maintaining homeostasis in almost all cell types and tissues (1). TGF-β functions via transmembrane serine/threonine kinase receptors, the type I and type II receptors (TGF-βRI and TGF-βRII) (2) and intracellular Smad transcriptional regulators (3). Increasing evidence has indicated that TGF-β is involved in the redox system in benign and tumor cells, in terms of that TGF-β can induce production of reactive oxygen species (ROS) which stimulates proliferation, invasion, migration and angiogenesis and evade apoptosis in cancer cells (4). TGF-β1 can stimulate a rapid increase in ROS generation to induce kidney myofibroblast activation and matrix synthesis (5). In renal tubular epithelial cells, TGF-β1 induces cellular ROS and mediates the epithelial-mesenchymal transition (EMT). All these effects can be abrogated by antioxidants (6). Low levels of ROS play a very important role in keeping normal cell proliferation by regulating cellular signaling. A great body of evidence indicates that production of ROS is increased in cancer cells and elevated ROS may facilitate tumor cell growth (7). However, a higher level of ROS may act reversely to induce an apoptotic response of tumor cells. Moderate ROS levels provide tumor cells with the advantage to maintain survival. Glutathione peroxidases (GPxs) are of the most important antioxidative enzyme families which can modulate cellular ROS levels to keep the redox balance in tumor cells.GPx-1 is the first identified selenoprotein and is expressed in most cells (8-10). GPx-1 is classified as an antioxidant enzyme and exerts its role to prevent the initiation of cancer by ROS-mediated DNA damage. Previous studies have suggested that GPx-1 is altered in several types of cancer cells (11,12) and overexpres...

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Targeting the transforming growth factor-β signaling pathway in human cancer

Cited by 245 publications

References 107 publications

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

Association between transforming growth factor-β1 expression and the clinical features of triple negative breast cancer

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

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