Hiroyuki Takeda1,2, Masashi Okada3, Shuhei Suzuki1,2, Kenta Kuramoto1, Hirotsugu Sakaki1,4, Hikaru Watarai1,5, Tomomi Sanomachi1, Shizuka Seino1,6, Takashi Yoshioka2, Chifumi Kitanaka3,6. 1. Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan. 2. Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan. 3. 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. 4. Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan. 5. Second Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan. 6. Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Small molecule inhibitor-mediated targeting of ROCK may be a viable strategy to overcome cancer chemoresistance through down-regulation of survivin. Copyright
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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 humancancer cell lines. CONCLUSION: Small molecule inhibitor-mediated targeting of ROCK may be a viable strategy to overcome cancer chemoresistance through down-regulation of survivin. Copyright
Authors: Elizabeth A Mazzio; Charles A Lewis; Rashid Elhag; Karam F Soliman Journal: Cancer Genomics Proteomics Date: 2018 Jul-Aug Impact factor: 3.395