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Tytuł:
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Dysfunctional activity of classical DNA end-joining renders acquired resistance to carboplatin in human ovarian cancer cells.
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Autorzy:
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Yoon MJ; Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Cha H; Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Ahn J; Department of Biochemistry, Research Institute for Basic Medical Science, School of Medicine, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Lee D; Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Jeong HS; Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Koo HS; Department of Obstetrics and Gynaecology, CHA Bundang Medical Center, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Kang YJ; Department of Biochemistry, Research Institute for Basic Medical Science, School of Medicine, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea; Department of Obstetrics and Gynaecology, CHA Bundang Medical Center, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea. Electronic address: .
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Źródło:
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Cancer letters [Cancer Lett] 2021 Nov 01; Vol. 520, pp. 267-280. Date of Electronic Publication: 2021 Aug 08.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
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MeSH Terms:
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Carboplatin/*pharmacology
Ovarian Neoplasms/*drug therapy
Receptors, Androgen/*genetics
ATP Binding Cassette Transporter, Subfamily B/genetics ; Carboplatin/adverse effects ; Cell Line, Tumor ; DNA Damage/drug effects ; DNA End-Joining Repair/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology
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Contributed Indexing:
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Keywords: Chemoresistance; DNA damage Response; DNA repair; Non-homologous end joining; Ovarian cancer
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Substance Nomenclature:
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0 (ABCB1 protein, human)
0 (AR protein, human)
0 (ATP Binding Cassette Transporter, Subfamily B)
0 (Receptors, Androgen)
BG3F62OND5 (Carboplatin)
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Entry Date(s):
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Date Created: 20210810 Date Completed: 20220107 Latest Revision: 20220107
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Update Code:
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20240105
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DOI:
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10.1016/j.canlet.2021.08.003
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PMID:
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34375710
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Ovarian cancer is the deadliest gynecological malignancy worldwide. Although chemotherapy is required as the most standard treatment strategy for ovarian cancer, the survival rates are very low, largely because of high incidence of recurrence due to resistance to conventional surgery and genotoxic chemotherapies. Carboplatin-resistant ovarian cancer cells were generated by continuous treatment over six months. Carboplatin-resistance induced morphological alterations and promoted the rates of proliferation and migration of SKOV3 compared to the parental cells. Interestingly, carboplatin-resistant SKOV3 showed the high levels of γH2AX foci formed at the basal level, and the levels of γH2AX foci remained even after the recovery time, suggesting that the DNA damage response and repair machinery were severely attenuated by carboplatin-resistance. Surprisingly, the expression levels of XRCC4, a critical factor in non-homologous end joining (NHEJ) DNA repair, were significantly decreased in carboplatin-resistant SKOV3 compared with those in non-resistant controls. Furthermore, restoration of NHEJ in carboplatin-resistant SKOV3 by suppression of ABCB1 and/or AR re-sensitized carboplatin-resistant cells to genotoxic stress and reduced their proliferation ability. Our findings suggest that attenuation of the NHEJ DNA repair machinery mediated by resistance to genotoxic stress might be a critical cause of chemoresistance in patients with ovarian cancer.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
