Journal Article

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

Jimmy Y.C. Chow, Khai T. Quach, Betty L. Cabrera, Jennifer A. Cabral, Stayce E. Beck and John M. Carethers

in Carcinogenesis

Volume 28, issue 11, pages 2321-2327
Published in print November 2007 | ISSN: 0143-3334
Published online July 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm159
RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells

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Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-β might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFβ 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 TGFβ surface receptors. Cells were treated with TGFβ1 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. TGFβ 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. TGFβ 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. TGFβ-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFβ. TGFβ-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFβ-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.

Journal Article.  4917 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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