Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.
Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.
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DOI：
10.1016/j.cellsig.2021.109931
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发表时间：
2021-01
影响因子：
4.8
通讯作者：
Shanshan He;Gang Li-;A. Schätzlein;P. Humphrey;R. Weiss;I. Uchegbu;Darryl T. Martin
中科院分区：
文献类型：
--
作者：
Shanshan He;Gang Li-;A. Schätzlein;P. Humphrey;R. Weiss;I. Uchegbu;Darryl T. Martin
化疗耐药性是膀胱癌治疗发展的障碍之一。以前，我们发现糖蛋白-130（GP 130）在化疗耐药的膀胱癌细胞中过表达，并且敲低GP 130表达降低了细胞活力。在我们目前的工作中，我们发现GP 130的下调通过激活DNA修复信号使膀胱癌细胞对顺铂化疗敏感。我们进行了免疫组化，并证明了Ku 70，典型的非同源末端连接修复（c-NHEJ）的启动子和抑制细胞凋亡，和GP 130在人膀胱癌标本的水平之间的正相关性。通过SC 144（一种小分子抑制剂）与顺铂组合敲低GP 130增加了DNA损伤的数量，特别是DNA双链断裂，随后增加了细胞凋亡并降低了细胞活力。此外，GP 130抑制减弱Ku 70在膀胱癌和乳腺癌细胞以及转化的肾细胞中的表达。此外，我们制造了一种新的聚合物-脂质杂化递送系统，以促进GP 130 siRNA的递送，与Lipofectamine相比，具有相似的效率，但诱导的毒性较小。
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.