title: Inhibition of ERβ induces resistance to cisplatin by enhancing Rad51-mediated DNA repair in human medulloblastoma cell lines.
abstract: Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin-induced cytotoxicity in human medulloblastoma cell lines.
authors.affiliation: Neurological Cancer Research, Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilk
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Waligorska
authors.forename: Piotr
authors.initials: P
authors.lastname: Waligorski
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077267:Fulvestrant; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D000077267:Fulvestrant; D004958:Estradiol; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin