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.
Highlights
Medulloblastomas are the most common and aggressive intracranial tumors in children [1,2,3]
We have recently demonstrated that highlevels of estrogen receptor b (ERb) in medulloblastoma are associated with nuclear translocation of insulin receptor substrate 1 (IRS-1), and the involvement of nuclear IRS-1 in the inhibition of homologous recombination directed DNA repair (HRR) of double strand breaks (DSBs)
Results of this study demonstrate that human medulloblastoma cell lines develop resistance to cisplatin in the presence of a potential anticancer drug, estrogen receptor (ER) antagonist, ICI182,780
Summary
Medulloblastomas are the most common and aggressive intracranial tumors in children [1,2,3]. We have recently demonstrated that highlevels of ERb in medulloblastoma are associated with nuclear translocation of insulin receptor substrate 1 (IRS-1), and the involvement of nuclear IRS-1 (nIRS-1) in the inhibition of homologous recombination directed DNA repair (HRR) of double strand breaks (DSBs). This interference with the DNA repair process involves a direct interaction between nIRS-1 and the major enzymatic component of HRR, Rad51 [9]. This new finding indicates that ICI182,780, by improving HRR, allows more effective repair of cisplatin-inflicted DNA damage during the S phase, which may explain decrease in G2/M arrest, improved cell survival, and partial preservation of the clonogenic growth of Daoy cells after removal of the genotoxic agent
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