{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:13:29Z","timestamp":1791051209561,"version":"4.1.0"},"reference-count":38,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2008,4]]},"abstract":"<jats:p>Transforming growth factor-\u03b2 (TGF-\u03b2) suppresses growth via the TGF-\u03b2-SMAD pathway but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF-\u03b2 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-\u03b2 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-\u03b21 (10 ng\/ml) suppressed PTEN expression and increased cell proliferation. TGF-\u03b2-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-\u03b2, and PTEN downregulation by TGF-\u03b2 was specifically mediated by PKC-\u03b1. In parallel, TGF-\u03b2 rapidly induced an increase in cytoplasmic free calcium from intracellular stores, consistent with subsequent PKC-\u03b1 activation. The TGF-\u03b2-induced increase in cell migration was blocked by knockdown of PKC-\u03b1. Thus calcium-dependent PKC-\u03b1 mediates TGF-\u03b2-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-\u03b2-PKC-\u03b1-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.<\/jats:p>","DOI":"10.1152\/ajpgi.00411.2007","type":"journal-article","created":{"date-parts":[[2008,2,1]],"date-time":"2008-02-01T01:59:03Z","timestamp":1201831143000},"page":"G899-G905","source":"Crossref","is-referenced-by-count":61,"title":["TGF-\u03b2 mediates<i>PTEN<\/i>suppression and cell motility through calcium-dependent PKC-\u03b1 activation in pancreatic cancer cells"],"prefix":"10.1152","volume":"294","author":[{"given":"Jimmy Y. 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