title: Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine.
abstract: Targeting pathways regulating survivin expression, which has been implicated in multidrug resistance of cancer cells, is a promising strategy to overcome cancer chemoresistance. To date, the role of rho-associated protein kinases (ROCKs) in survivin expression remains largely unknown.
  
  
  
  The effects of ROCK inhibitors Y-27632 and fasudil on survivin expression and cell viability were determined by immunoblot analysis and dye exclusion, respectively, in PANC-1 CSLC, a cancer stem cell line derived from a serum-cultured, gemcitabine-sensitive pancreatic cancer cell line, PANC-1.
  
  
  
  siRNA-mediated knockdown of survivin revealed that the gemcitabine resistance of PANC-1 CSLC was dependent on survivin expression. Both Y-27632 and fasudil, reduced survivin expression in PANC-1 CSLC cells and sensitized them to gemcitabine. ROCK inhibition also reduced survivin expression in various other human cancer cell lines.
  
  
  
  Small molecule inhibitor-mediated targeting of ROCK may be a viable strategy to overcome cancer chemoresistance through down-regulation of survivin.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.|Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan ckitanak@med.id.yamagata-u.ac.jp m-okada@med.id.yamagata-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.|Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kuramoto
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.|Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Sakaki
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.|Second Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Watarai
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sanomachi
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.|Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan ckitanak@med.id.yamagata-u.ac.jp m-okada@med.id.yamagata-u.ac.jp.|Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077022:Survivin; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D000077022:Survivin; D003841:Deoxycytidine; D054460:rho-Associated Kinases; D000093542:Gemcitabine
keywords: ROK; apoptosis; chemosensitization; combination chemotherapy