OBJECTIVES: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation. METHODS: Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. RESULTS: Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway. CONCLUSIONS: Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.
OBJECTIVES: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation. METHODS:Humanpancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. RESULTS: Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway. CONCLUSIONS: Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.
Authors: Anatoly Urisman; Rebecca S Levin; John D Gordan; James T Webber; Hilda Hernandez; Yasushi Ishihama; Kevan M Shokat; Alma L Burlingame Journal: Mol Cell Proteomics Date: 2016-12-11 Impact factor: 5.911
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Authors: Richard Peter Owen; Michael Joseph White; David Tyler Severson; Barbara Braden; Adam Bailey; Robert Goldin; Lai Mun Wang; Carlos Ruiz-Puig; Nicholas David Maynard; Angie Green; Paolo Piazza; David Buck; Mark Ross Middleton; Chris Paul Ponting; Benjamin Schuster-Böckler; Xin Lu Journal: Nat Commun Date: 2018-10-15 Impact factor: 14.919
Authors: Maria Teresa De Angelis; Gianluca Santamaria; Elvira Immacolata Parrotta; Stefania Scalise; Michela Lo Conte; Sara Gasparini; Edoardo Ferlazzo; Umberto Aguglia; Clara Ciampi; Antonella Sgura; Giovanni Cuda Journal: J Cell Mol Med Date: 2019-09-19 Impact factor: 5.310