Carcinogenesis Advance Access originally published online on July 17, 2007
Carcinogenesis 2007 28(11):2321-2327; doi:10.1093/carcin/bgm159
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RAS/ERK modulates TGFß-regulated PTEN expression in human pancreatic adenocarcinoma cells
1 Division of Gastroenterology, Department of Medicine
2 Biomedical Sciences Program
3 Rebecca and John Moores Comprehensive Cancer Center, University of California, San Diego, MC 0063, 9500 Gilman Drive, La Jolla, CA 92093-0063, USA
4 VA San Diego Healthcare System, San Diego, CA 92161, USA
* To whom correspondence should be addressed. Tel: +858 534 3320; Fax: +858 534 3338; Email: jcarethers{at}ucsd.edu
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-ß might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFß 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 TGFß surface receptors. Cells were treated with TGFß1 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. TGFß 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. TGFß 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. TGFß-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFß. TGFß-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFß-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.
Abbreviations: Akt, ATP-dependent tyrosine kinases; DN, dominant negative; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PI3K, phosphatidylinositol-3-kinase; PCR, polymerase chain reaction; TGF, transforming growth factor
Received March 23, 2007; revised July 2, 2007; accepted July 3, 2007.
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