TGF-β mediatesPTENsuppression and cell motility through calcium-dependent PKC-α activation in pancreatic cancer cells
- 1 April 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 294 (4), G899-G905
- https://doi.org/10.1152/ajpgi.00411.2007
Abstract
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-α. 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.Keywords
This publication has 43 references indexed in Scilit:
- Cancer Statistics, 2007CA: A Cancer Journal for Clinicians, 2007
- PKCα mediates TGFβ-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11The Journal of cell biology, 2004
- Role of protein kinase C α in calcium induced keratinocyte differentiation: Defective regulation in squamous cell carcinomaJournal of Cellular Physiology, 2003
- Transforming growth factor-β1 regulation of growth zone chondrocytes is mediated by multiple interacting pathwaysBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2002
- TGF-? signaling in A549 lung carcinoma cells: lipid second messengersJournal of Cellular Biochemistry, 2000
- Infrequent Genetic Alterations of thePTEN/MMAC1Gene in Japanese Patients with Primary Cancers of the Breast, Lung, Pancreas, Kidney, and OvaryJapanese Journal of Cancer Research, 1997
- Inhibition of Expression of PKC-α by Antisense mRNA Is Associated with Diminished Cell Growth and Inhibition of Amylase Secretion by AR4-2J CellsExperimental Cell Research, 1997
- Inhibition of protein kinase C μ by various inhibitors. Inhibition from protein kinase c isoenzymesFEBS Letters, 1996
- Role of protein kinase C in transforming growth factor‐β1 induction of carcinoembryonic antigen in human colon carcinoma cellsJournal of Cellular Physiology, 1992
- Cloning and expression of multiple protein kinase C cDNAsCell, 1986