Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13), p.3185-3191
Main Authors: Mukherjee, Anirban, Huynh, Van, Gaines, Kailee, Reh, Wade Alan, Vasquez, Karen M
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis
Cell Proliferation
Cisplatin - pharmacology
Drug Resistance, Neoplasm
Female
HMGB3 Protein - antagonists & inhibitors
HMGB3 Protein - genetics
HMGB3 Protein - metabolism
Humans
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
RNA, Small Interfering - genetics
Tumor Cells, Cultured
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Summary: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 and , 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-19-0542