Dysfunctional activity of classical DNA end-joining renders acquired resistance to carboplatin in human ovarian cancer cells. 2021

Min-Ji Yoon, and Hwijae Cha, and Jungho Ahn, and Danbi Lee, and Hyun-Seok Jeong, and Hwa Seon Koo, and Youn-Jung Kang
Department of Biomedical Science, School of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.

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.

UI MeSH Term Description Entries
D010051 Ovarian Neoplasms Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS. Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D011944 Receptors, Androgen Proteins, generally found in the CYTOPLASM, that specifically bind ANDROGENS and mediate their cellular actions. The complex of the androgen and receptor migrates to the CELL NUCLEUS where it induces transcription of specific segments of DNA. Androgen Receptors,5 alpha-Dihydrotestosterone Receptor,Androgen Receptor,Dihydrotestosterone Receptors,Receptor, Testosterone,Receptors, Androgens,Receptors, Dihydrotestosterone,Receptors, Stanolone,Stanolone Receptor,Testosterone Receptor,5 alpha Dihydrotestosterone Receptor,Androgens Receptors,Receptor, 5 alpha-Dihydrotestosterone,Receptor, Androgen,Receptor, Stanolone,Stanolone Receptors,alpha-Dihydrotestosterone Receptor, 5
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015972 Gene Expression Regulation, Neoplastic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue. Neoplastic Gene Expression Regulation,Regulation of Gene Expression, Neoplastic,Regulation, Gene Expression, Neoplastic
D016190 Carboplatin An organoplatinum compound that possesses antineoplastic activity. cis-Diammine(cyclobutanedicarboxylato)platinum II,Blastocarb,CBDCA,Carboplat,Carbosin,Carbotec,Ercar,JM-8,NSC-241240,Nealorin,Neocarbo,Paraplatin,Paraplatine,Platinwas,Ribocarbo,JM 8,JM8,NSC 241240,NSC241240
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D059766 DNA End-Joining Repair The repair of DOUBLE-STRAND DNA BREAKS by rejoining the broken ends of DNA to each other directly. Non-Homologous DNA End-Joining,End-Joining DNA Repair,MMEJ DNA Repair,Microhomology-Mediated End Joining Repair,NHEJ DNA Repair,Nonhomologous DNA End-Joining,DNA End Joining Repair,DNA End-Joining, Non-Homologous,DNA End-Joining, Nonhomologous,DNA Repair, End-Joining,DNA Repair, MMEJ,DNA Repair, NHEJ,End Joining DNA Repair,End-Joining Repair, DNA,End-Joining, Non-Homologous DNA,Microhomology Mediated End Joining Repair,Non Homologous DNA End Joining,Nonhomologous DNA End Joining,Repair, DNA End-Joining,Repair, End-Joining DNA,Repair, MMEJ DNA,Repair, NHEJ DNA
D018435 ATP Binding Cassette Transporter, Subfamily B A subfamily of transmembrane proteins from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS that are closely related in sequence to ATP BINDING CASSETTE TRANSPORTER, SUBFAMILY B, MEMBER 1. When overexpressed, they function as ATP-dependent efflux pumps able to extrude lipophilic drugs (especially ANTINEOPLASTIC AGENTS) from cells, causing multidrug resistance (DRUG RESISTANCE, MULTIPLE). Although ATP BINDING CASSETTE TRANSPORTER, SUBFAMILY B share functional similarities to MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS they are two distinct subclasses of ATP-BINDING CASSETTE TRANSPORTERS, and have little sequence homology. Multidrug Resistance Proteins,P-Glycoproteins,ATP Binding Cassette Transporter, Sub-Family B,ATP-Binding Cassette, Sub-Family B Proteins,ATP Binding Cassette Transporter, Sub Family B,ATP Binding Cassette, Sub Family B Proteins,P Glycoproteins

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