RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells

被引:80
作者
Chow, Jimmy Y. C.
Quach, Khai T.
Cabrera, Betty L.
Cabral, Jennifer A.
Beck, Stayce E.
Carethers, John M.
机构
[1] Univ Calif San Diego, Dept Med, Div Gastroenterol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Program Biomed Sci, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Rebecca & John Moores Comprehens Canc Ctr, La Jolla, CA 92093 USA
[4] VA San Diego Healthcare Syst, San Diego, CA 92161 USA
关键词
D O I
10.1093/carcin/bgm159
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGF beta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGF beta surface receptors. Cells were treated with TGF beta 1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGF beta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGF beta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGF beta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGF beta. TGF beta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGF beta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.
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收藏
页码:2321 / 2327
页数:7
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