Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin
Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin
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DOI：
10.1158/0008-5472.can-19-0542
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发表时间：
2019-07-01
期刊：
影响因子：
11.2
通讯作者：
Vasquez, Karen M.
中科院分区：
文献类型：
--
作者：
Mukherjee, Anirban;Van Huynh;Vasquez, Karen M.
卵巢癌的化疗方案通常包括使用DNA链间交联剂(如铂类药物)或DNA双链断裂诱导剂。不幸的是，大多数患者未能对治疗保持持久的反应，部分原因是耐药性，导致存活率很低。在这项研究中，我们报告了通过靶向染色质相关的高迁移率族蛋白3(HMGB3)可以恢复顺铂耐药卵巢癌细胞对顺铂的敏感性。HMGB蛋白与卵巢癌的发病机制和预后密切相关，而HMGB3在肿瘤细胞中表达上调，使其成为潜在的选择性治疗靶点。HMGB3在顺铂敏感和耐药细胞中的缺失导致ATR和CHK1激酶转录下调，从而减弱ATR/CHK1/p-CHK1 DNA损伤信号通路。HMGB3与ATR和CHK1的启动子区域相关，提示HMGB3在转录调控中发挥新的作用。此外，HMGB3缺失显著增加顺铂耐药的A2780/CP70细胞在顺铂治疗后的凋亡率。综上所述，我们的结果表明，靶向缺失HMGB3可以降低人卵巢癌细胞对顺铂的耐药性，增加肿瘤细胞对铂类药物的敏感性。意义：本研究表明，靶向HMGB3是克服卵巢癌化疗耐药的一种潜在的治疗策略。
Chemotherapeutic regimens for ovarian cancer often include the use of DNA interstrand crosslink-inducing agents (e.g., platinum drugs) or DNA double-strand break-inducing agents. Unfortunately, the majority of patients fail to maintain a durable response to treatment, in part, due to drug resistance, contributing to a poor survival rate. In this study, we report that cisplatin sensitivity can be restored in cisplatin-resistant ovarian cancer cells by targeting the chromatin-associated high-mobility group box 3 (HMGB3) protein. HMGB proteins have been implicated in the pathogenesis and prognosis of ovarian cancer, and HMGB3 is often upregulated in cancer cells, making it a potential selective target for therapeutic intervention. Depletion of HMGB3 in cisplatin-sensitive and cisplatin-resistant cells resulted in transcriptional downregulation of the kinases ATR and CHK1, which attenuated the ATR/CHK1/p-CHK1 DNA damage signaling pathway. HMGB3 was associated with the promoter regions of ATR and CHK1, suggesting a new role for HMGB3 in transcriptional regulation. Furthermore, HMGB3 depletion significantly increased apoptosis in cisplatin-resistant A2780/CP70 cells after cisplatin treatment. Taken together, our results indicate that targeted depletion of HMGB3 attenuates cisplatin resistance in human ovarian cancer cells, increasing tumor cell sensitivity to platinum drugs.Significance: This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.