Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine

• Published in: Anticancer research Vol. 36; no. 12; pp. 6311 - 6318
• Main Authors: Takeda, Hiroyuki, Okada, Masashi, Suzuki, Shuhei, Kuramoto, Kenta, Sakaki, Hirotsugu, Watarai, Hikaru, Sanomachi, Tomomi, Seino, Shizuka, Yoshioka, Takashi, Kitanaka, Chifumi
• Format: Journal Article
• Language: English
• Published: Greece 01.12.2016
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; rho-Associated Kinases - antagonists & inhibitors; apoptosis; chemosensitization; combination chemotherapy; ROK
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.11227

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.