Inhibition of pancreatic adenocarcinoma cellular invasiveness by blebbistatin: a novel myosin II inhibitor.
Blebbistatin is a novel 1-phenyl-2-pyrrolidinone derivative capable of inhibiting non-muscle myosin II activity with a high degree of specificity. We examined the effects of blebbistatin on pancreatic adenocarcinoma cellular migration, invasion, adhesion, and spreading. Blebbistatin dose-dependently inhibited cellular migration and invasiveness, quantified by modified Boyden chamber assay. Matrix metalloproteinase 2 and 9 activities were unaffected by blebbistatin and cellular proliferation was inhibited only by concentrations of blebbistatin exceeding those required to inhibit myosin II activity and to interfere with migration and invasion. While blebbistatin treatment did not affect cell adhesion to the extracellular matrix component fibronectin, it markedly impaired cell spreading on this substrate. Cell surface expression of the archetypal fibronectin receptor (alpha(5)beta(1) integrin) was unaffected by blebbistatin. Our observations illustrate the critical role of non-muscle myosin II in pancreatic adenocarcinoma cellular invasiveness and extracellular matrix interaction and suggest that therapeutic strategies targeting myosin II warrant further investigation.
Duxbury
Mark S
MS
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ashley
Stanley W
SW
Whang
Edward E
EE
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D024462:Myosin Type II / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; C472645:blebbistatin; D024462:Myosin Type II