期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 294, 期 4, 页码 G899-G905出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00411.2007
关键词
transforming growth factor-beta; PTEN; protein kinase C
资金
- NIDDK NIH HHS [R01 DK067287, DK-080506, DK-067287, K01 DK073090-01A1, R01 DK067287-02, K01 DK073090, R24 DK080506, K01-DK-073090, R24 DK080506-02] Funding Source: Medline
TGF-beta mediates PTEN suppression and cell motility through calcium-dependent PKC-alpha activation in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 294: G899-G905, 2008. First published January 31, 2008; doi: 10.1152/ajpgi.00411.2007.-Transforming growth factor-beta (TGF-beta) suppresses growth via the TGF-beta-SMAD pathway but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF-beta 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-beta 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-beta 1 ( 10 ng/ml) suppressed PTEN expression and increased cell proliferation. TGF-beta-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-beta, and PTEN downregulation by TGF-beta was specifically mediated by PKC-alpha. In parallel, TGF-beta rapidly induced an increase in cytoplasmic free calcium from intracellular stores, consistent with subsequent PKC-alpha activation. The TGF-beta-induced increase in cell migration was blocked by knockdown of PKC-alpha. Thus calcium- dependent PKC-alpha mediates TGF-beta-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-beta-PKC-alpha- PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.
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