Enhancement of cisplatin-induced cytotoxicity by ROCK inhibitor through suppression of focal adhesion kinase-independent mechanism in lung carcinoma cells.
Intracellular signaling through Rho-associated coiled-coil forming kinase (ROCK) is a target of antimetastatic therapy and is proposed to be involved in carcinogenesis. Focal adhesion kinase (FAK) functions downstream of ROCK and participates in anti-apoptotic signaling. We hypothesized that a specific ROCK inhibitor, Y-27632, may exert a pro-apoptotic effect in combination with anticancer agents through the suppression of FAK. A549 lung carcinoma cells were treated with Y-27632 and cisplatin. The simultaneous combination did not exert any additional effect, whereas sequential treatment, in which cisplatin followed Y-27632, enhanced cytotoxicity in concentration- and time-dependent manner. Y-27632 did not suppress tyrosine phosphorylation of FAK in A549-FAK, the active form of FAK expressing A549 cells, as observed in parental cells. Nevertheless, the pretreatment of A549-FAK cells with Y-27632 still enhanced cisplatin-induced cytotoxicity. It was concluded that the ROCK inhibitor enhances cisplatin-induced cytotoxicity through FAK suppression-independent mechanism(s). These observations raise the possibility that the inhibition of the ROCK-mediated signal enhances the effect of anti-cancer agents in addition to its antimetastatic property.
Igishi
Tadashi
T
Third Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan. igishi@grape.med.tottori-u.ac.jp
Mikami
Masaaki
M
Murakami
Kaori
K
Matsumoto
Shingo
S
Shigeoka
Yasushi
Y
Nakanishi
Hirofumi
H
Yasuda
Kazuhito
K
Gutkind
J Silvio
JS
Hitsuda
Yutaka
Y
Shimizu
Eiji
E
D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000188:drug therapy*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002945:Cisplatin