Department of Urology, Yale University, New Haven, CT, USA.
School of Pharmacy, University College London, London, UK.
Cell Signal. 2021 May;81:109931. doi: 10.1016/j.cellsig.2021.109931. Epub 2021 Jan 30.
Chemoresistance is one of the barriers for the development of bladder cancer treatments. Previously, we showed that glycoprotein-130 (GP130) is overexpressed in chemoresistant bladder cancer cells and that knocking down GP130 expression reduced cell viability. In our current work, we showed that down-regulation of GP130 sensitized bladder cancer cells to cisplatin-based chemotherapy by activating DNA repair signaling. We performed immunohistochemistry and demonstrated a positive correlation between the levels of Ku70, an initiator of canonical non-homologous end joining repair (c-NHEJ) and suppressor of apoptosis, and GP130 in human bladder cancer specimens. GP130 knockdown by SC144, a small molecule inhibitor, in combination with cisplatin, increased the number of DNA lesions, specifically DNA double-stranded breaks, with a subsequent increase in apoptosis and reduced cell viability. Furthermore, GP130 inhibition attenuated Ku70 expression in bladder and breast cancer cells as well as in transformed kidney cells. In addition, we fabricated a novel polymer-lipid hybrid delivery system to facilitate GP130 siRNA delivery that had a similar efficiency when compared with Lipofectamine, but induced less toxicity.
化学耐药性是膀胱癌治疗发展的障碍之一。之前，我们发现糖蛋白 130（GP130）在化疗耐药的膀胱癌细胞中过表达，敲低 GP130 的表达会降低细胞活力。在目前的工作中，我们发现下调 GP130 可以通过激活 DNA 修复信号来增强顺铂为基础的化疗药物对膀胱癌细胞的敏感性。我们进行了免疫组织化学分析，并在人类膀胱癌标本中证明了 Ku70（经典非同源末端连接修复（c-NHEJ）的起始因子和凋亡抑制因子）与 GP130 之间存在正相关。小分子抑制剂 SC144 下调 GP130 的表达与顺铂联合使用，增加了 DNA 损伤的数量，特别是双链 DNA 断裂，随后导致细胞凋亡增加和细胞活力降低。此外，GP130 抑制作用可减弱膀胱癌、乳腺癌细胞以及转化的肾细胞中的 Ku70 表达。另外，我们构建了一种新型聚合物-脂质混合递药系统，促进 GP130 siRNA 的递释，其效率与 Lipofectamine 相当，但诱导的毒性更小。
