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Ref Type | Journal Article | ||||||||||||
PMID | (15289325) | ||||||||||||
Authors | Subramanian G, Schwarz RE, Higgins L, McEnroe G, Chakravarty S, Dugar S, Reiss M | ||||||||||||
Title | Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. | ||||||||||||
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Abstract Text | Transforming growth factor-beta (TGF-beta) suppresses tumor formation by blocking cell cycle progression and maintaining tissue homeostasis. In pancreatic carcinomas, this tumor suppressive activity is often lost by inactivation of the TGF-beta-signaling mediator, Smad4. We found that human pancreatic carcinoma cell lines that have undergone deletion of MADH4 constitutively expressed high endogenous levels of phosphorylated receptor-associated Smad proteins (pR-Smad2 and pR-Smad3), whereas Smad4-positive lines did not. These elevated pR-Smad levels could not be attributed to a decreased dephosphorylation rate nor to increased expression of TGF-beta type I (TbetaR-I) or type II (TbetaR-II) receptors. Although minimal amounts of free bioactive TGF-beta1 and TGF-beta2 were detected in conditioned medium, treatment with a pan-specific (but not a TGF-beta3 specific) TGF-beta-neutralizing antibody and with anti-alpha(V)beta(6) integrin antibody decreased steady-state pSmad2 levels and activation of a TGF-beta-inducible reporter gene in neighboring cells, respectively. Thus, activation of TGF-beta at the cell surface was responsible for the increased autocrine endogenous and paracrine signaling. Blocking TbetaR-I activity using a selective kinase inhibitor (SD-093) strongly decreased the in vitro motility and invasiveness of the pancreatic carcinoma cells without affecting their growth characteristics, morphology, or the subcellular distribution of E-cadherin and F-actin. Moreover, exogenous TGF-beta strongly stimulated in vitro invasiveness of BxPC-3 cells, an effect that could also be blocked by SD-093. Thus, the motile and invasive properties of Smad4-deficient pancreatic cancer cells are at least partly driven by activation of endogenous TGF-beta signaling. Therefore, targeting the TbetaR-I kinase represents a potentially powerful novel therapeutic approach for the treatment of this disease. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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SD-093 | TGFBR1 inhibitor 16 | SD-093 is an ATP competitive inhibitor of TGFBR1, which may promote immune response and inhibit tumor growth (PMID: 15183116, PMID: 15289325, PMID: 16857807). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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