Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.

Abstract

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.

• Authors: Shanshan He, Gang Li, Andreas G Schätzlein, Peter A Humphrey, Robert M Weiss, Ijeoma F Uchegbu, Darryl T Martin
• Journal: Cellular signalling (Cell Signal) Vol. 81 Pg. 109931 (05 2021) ISSN: 1873-3913 [Electronic] England
• PMID: 33529758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• IL6ST protein, human
• Neoplasm Proteins
• Cytokine Receptor gp130
• Xrcc6 protein, human
• Ku Autoantigen
• Cisplatin

Topics

• Apoptosis (drug effects)
• Cisplatin (pharmacology)
• Cytokine Receptor gp130 (biosynthesis)
• DNA Repair
• Down-Regulation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Ku Autoantigen (metabolism)
• MCF-7 Cells
• Male
• Neoplasm Proteins (metabolism)
• Signal Transduction (drug effects)
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology)