Myosin light chain kinase inhibitors can block invasion and adhesion of human pancreatic cancer cell lines.
BACKGROUND
Invasion and metastasis of pancreatic cancer (PC) require cell motility and adhesion, which depend on the activity of cytoskeleton. A cytoskeletal component indispensable for these processes is myosin II, the cytoplasmic analogue of smooth and skeletal muscle myosin.


OBJECTIVE
Because the activity of myosin II is accelerated by phosphorylation of myosin II on its regulatory light chain (RLC) by myosin light chain kinase (MLCK), we used two specific MLCK inhibitors, ML-7 and ML-9, for suppression of motility and adhesion of PC cell lines.


RESULTS
Both drugs were potent inhibitors, as measured by in vitro motility assay and adhesion assay. When treated with the same concentration of ML-7, the PC cells were rounded up, and the number of stress fibers was reduced markedly. The in vitro migration and adhesion of PC cells were inhibited by ML-7 and ML-9 in a dose-dependent manner, supporting a specific and competitive inhibition of MLCK by these drugs. The inhibition occurred at nontoxic concentrations.


CONCLUSIONS
These results highlight the importance of myosin II in the invasion and metastasis of PC cells and suggest the possibility that blocking of myosin II activity by a specific MLCK inhibitor may be a therapeutic strategy for preventing the invasion and metastasis of PC.
Kaneko
Kenzo
K
Department of Gastroenterology, Division of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyaga, Japan. kkaneko@int3.tohoku.ac.jp
Satoh
Kennichi
K
Masamune
Atsushi
A
Satoh
Akihiko
A
Shimosegawa
Tooru
T
D001381:Azepines / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D009281:Naphthalenes / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D001381:Azepines; D004791:Enzyme Inhibitors; D019012:Integrin beta1; D009281:Naphthalenes; C056218:ML 9; C070571:ML 7; D009219:Myosin-Light-Chain Kinase