Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine.
Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine.
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DOI：
10.21873/anticanres.11227
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发表时间：
2016-12
影响因子：
2
通讯作者：
Hiroyuki Takeda;M. Okada;Shuhei Suzuki;Kenta Kuramoto;Hirotsugu Sakaki;Hikaru Watarai;Tomomi Sanomachi;Shizuka Seino;T. Yoshioka;C. Kitanaka
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文献类型：
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作者：
Hiroyuki Takeda;M. Okada;Shuhei Suzuki;Kenta Kuramoto;Hirotsugu Sakaki;Hikaru Watarai;Tomomi Sanomachi;Shizuka Seino;T. Yoshioka;C. Kitanaka
靶向调节存活素表达的途径（其与癌细胞的多药耐药性有关）是克服癌症化疗耐药性的有希望的策略。迄今为止，rho相关蛋白激酶（ROCK）在生存素表达中的作用在很大程度上仍然未知。材料和方法ROCK抑制剂Y-27632和法舒地尔对生存素表达和细胞活力的影响分别通过免疫印迹分析和染料排斥法在PANC-1 CSLC中测定，PANC-1 CSLC是一种来源于血清培养的吉西他滨敏感性胰腺癌细胞系PANC-1的癌症干细胞系。结果siRNA介导的survivin基因敲减显示PANC-1 CSLC的吉西他滨耐药依赖于survivin的表达。Y-27632和法舒地尔都降低了PANC-1 CSLC细胞中的存活素表达，并使它们对吉西他滨敏感。ROCK抑制还降低了各种其他人类癌细胞系中的存活素表达。结论小分子靶向ROCK可能是通过下调survivin来克服肿瘤耐药的一种可行策略。
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.