TY - JOUR
T1 - Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor lefty
AU - Miyata, Naoteru
AU - Azuma, Toshifumi
AU - Hozawa, Shigenari
AU - Higuchi, Hajime
AU - Yokoyama, Akiko
AU - Kabashima, Ayano
AU - Igarashi, Toru
AU - Saeki, Keita
AU - Hibi, Toshifumi
PY - 2012/7/1
Y1 - 2012/7/1
N2 - 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 upregulation, 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.
AB - 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 upregulation, 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.
KW - C-Jun N-terminal kinase
KW - Extracellular signal-regulated kinase
KW - P38 map kinase
KW - Phosphoinositide 3-kinase
KW - Smad-dependent pathway
KW - Small interfering RNA
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U2 - 10.1097/MPA.0b013e31823b66d3
DO - 10.1097/MPA.0b013e31823b66d3
M3 - Article
C2 - 22441145
AN - SCOPUS:84863717210
SN - 0885-3177
VL - 41
SP - 745
EP - 752
JO - Pancreas
JF - Pancreas
IS - 5
ER -
