title: Extracellular pressure stimulates colon cancer cell proliferation via a mechanism requiring PKC and tyrosine kinase signals.
abstract: Pressure in colonic tumours may increase during constipation, obstruction or peri-operatively. Pressure enhances colonocyte adhesion by a c-Src- and actin-cytoskeleton-dependent PKC-independent pathway. We hypothesized that pressure activates mitogenic signals.
  
  
  METHODS
  Malignant colonocytes on a collagen I matrix were subjected to 15 mmHg pressure. ERK, p38, c-Src and Akt phosphorylation and PKCalpha redistribution were assessed by western blot after 30 min and PKC activation by ELISA. Cells were counted after 24 h and after inhibition of each signal, tyrosine phosphorylation or actin depolymerization.
  
  
  RESULTS
  Pressure time-dependently increased SW620 and HCT-116 cell counts on collagen or fibronectin (P < 0.01). Pressure increased the SW620 S-phase fraction from 28 +/- 1 to 47 +/- 1% (P = 0.0002). Pressure activated p38, ERK, and c-Src (P < 0.05 each) but not Akt/PKB. Pressure decreased cytosolic PKC activity, and translocated PKCalpha to a membrane fraction. Blockade of p38, ERK, c-Src or PI-3-K or actin depolymerization did not inhibit pressure-stimulated proliferation. However, global tyrosine kinase blockade (genistein) and PKC blockade (calphostin C) negated pressure-induced proliferation.
  
  
  CONCLUSIONS
  Extracellular pressure stimulates cell proliferation and activates several signals. However, the mitogenic effect of pressure requires only tyrosine kinase and PKCalpha activation. Pressure may modulate colon cancer growth and implantation by two distinct pathways, one stimulating proliferation and the other promoting adhesion.
authors.affiliation: Wayne State University School of Medicine, John D. Dingell VAMC, Detroit, MI 48201-1932, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Walsh
authors.forename: R K-Y
authors.initials: RK
authors.lastname: Woo
authors.forename: R
authors.initials: R
authors.lastname: Gomez
authors.forename: M D
authors.initials: MD
authors.lastname: Basson
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000201:enzymology* / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011312:Pressure / Q000009:adverse effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human; C496628:PRKCA protein, human