TGF-[beta] mediates PTEN suppression and cell motility through calcium-dependent PKC-[alpha] activation in pancreatic cancer cells

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...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2008-04, Vol.294 (4), p.G899
Main Authors: Chow, Jimmy Y C, Dong, Hui, Quach, Khai T, Nguyen, Phuoc Nam Van, Chen, Kevin, Carethers, John M
Format: Article
Language:English
Subjects:
Cell adhesion & migration
Cell growth
Cells
Gene expression
Kinases
Pancreatic cancer
Tumors
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Summary: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-α activation. The TGF-β-induced increase in cell migration was blocked by knockdown of PKC-α. Thus calcium-dependent PKC-α mediates TGF-β-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-β-PKC-α-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize. [PUBLICATION ABSTRACT]
ISSN:0193-1857
1522-1547