Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating aspartate beta-hydroxylase.

Autor: Nagaoka K; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA; Department of Gastroenterology & Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Bai X; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Liu D; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Cao K; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Mulla J; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Ji C; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Chen H; Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA., Nisar MA; Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA., Bay A; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Mueller W; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Hildebrand G; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Gao JS; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Lu S; Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, RI, 02903, USA., Setoyama H; Department of Gastroenterology & Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Tanaka Y; Department of Gastroenterology & Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Wands JR; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA., Huang CK; Liver Research Center, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA; Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA. Electronic address: Chuang17@tulane.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Jan 01; Vol. 580, pp. 216493. Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1016/j.canlet.2023.216493
Abstrakt: Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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