Carcinogenesis Advance Access published online on July 17, 2007
Carcinogenesis, 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 Rebecca and John Moores Comprehensive Cancer Center, University of California, San Diego
3 Biomedical Sciences Program, University of California, San Diego
4 VA San Diego Healthcare System
Correspondence: John M. Carethers, M.D., Division of Gastroenterology, MC 0063, 9500 Gilman Drive, La Jolla, CA 92093-0063, Email: jcarethers{at}ucsd.edu, Phone: (858) 534-3320, Fax: (858) 534-3338
PTEN is rarely mutated in pancreatic cancers, but its regulation by TGFß 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-Akt, Akt, and PTEN antibodies. PTEN mRNA levels were assessed by RT-PCR. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative 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 hrs through transcriptional reduction of PTEN mRNA that was evident by 6 hrs. TGFß-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared to 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 downregulation 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.
Key Words: Transforming growth factor beta • PTEN • ERK MAP kinase • RAS • PI3K • pancreatic cancer
Received March 23, 2007; revised July 2, 2007; accepted July 3, 2007.
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