title: Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells.
abstract: Rho, a Ras-related small GTPase, and Rho-associated coiled coil-containing protein kinase (Rho kinase, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Rho/ROCK kinases also play roles in proliferation, differentiation, apoptosis and oncogenic transformation. In the present study, we have shown that Rho/ROCK pathway inhibition by fasudil, an orally administered inhibitor of Rho kinases, enhanced cisplatin-induced growth inhibition and apoptosis in human ovarian cancer cell lines. Fasudil inhibited hypoxia inducible factor (HIF)-1α protein expression. Knockdown of RhoA, ROCK1 or ROCK2 also attenuated the expression of HIF-1α. Furthermore, knockdown of HIF-1α using small interfering RNA enhanced cisplatin-induced growth inhibition and apoptosis as did inhibition of the Rho/ROCK pathway by fasudil, the Rho/ROCK inhibitor Y27632, or by Rho/ROCK knockdown. Therefore, the Rho/ROCK pathway may modulate HIF-1α signal transduction and blockade of Rho/ROCK enhances the efficacy of cisplatin by inhibiting HIF-1α in ovarian cancer cells. Our findings suggested that the Rho/ROCK pathway may be a new target for molecular targeting therapies against ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Yamagata University, Yamagata, Japan. oota-t@med.id.yamagata-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ohta
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tae
authors.initials: T
authors.lastname: Shibuya
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Amita
authors.forename: Noriko
authors.initials: N
authors.lastname: Henmi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; C066737:RHOA protein, human; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C049347:fasudil; D002945:Cisplatin