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Am J Physiol Gastrointest Liver Physiol 294: G899-G905, 2008. First published January 31, 2008; doi:10.1152/ajpgi.00411.2007
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HORMONES AND SIGNALING

TGF-β mediates PTEN suppression and cell motility through calcium-dependent PKC-{alpha} activation in pancreatic cancer cells

Jimmy Y. C. Chow,1 Hui Dong,1 Khai T. Quach,1 Phuoc Nam Van Nguyen,1 Kevin Chen,1 and John M. Carethers1,2,3

1Division of Gastroenterology Department of Medicine and 2Rebecca and John Moores Comprehensive Cancer Center University of California San Diego, and 3Veterans Affairs San Diego Healthcare System, San Diego, California

Submitted 12 September 2007 ; accepted in final form 30 January 2008

Transforming growth factor-β (TGF-β) suppresses growth via the TGF-β-SMAD pathway but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF-β also downregulates the tumor suppressor PTEN that is rarely mutated in sporadic pancreatic cancer; this downregulation may mediate cell proliferation and invasiveness, but the mechanism is unknown. Here, we examined whether TGF-β modulation of PTEN was mediated by protein kinase C (PKC). We have previously demonstrated that SMAD4-null BxPc-3 pancreatic cancer cells treated with TGF-β1 (10 ng/ml) suppressed PTEN expression and increased cell proliferation. TGF-β-treated cells were examined for PKC activation and its coupling to PTEN expression, utilizing pharmacological and knockdown methods. Calcium mobilization and cell migration were also examined. In BxPc-3 cells, only two PKC isoforms were activated by TGF-β, and PTEN downregulation by TGF-β was specifically mediated by PKC-{alpha}. In parallel, TGF-β rapidly induced an increase in cytoplasmic free calcium from intracellular stores, consistent with subsequent PKC-{alpha} activation. The TGF-β-induced increase in cell migration was blocked by knockdown of PKC-{alpha}. Thus calcium-dependent PKC-{alpha} mediates TGF-β-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-β-PKC-{alpha}-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.

transforming growth factor-β; PTEN; protein kinase C


Addressfor reprint requests and other correspondence: J. M. Carethers, Div. of Gastroenterology, UCSD, Univ. Center 303, MC0063, 9500 Gilman Dr., La Jolla, CA 92093-0063 (e-mail: jcarethers{at}ucsd.edu)






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