title: Impaired homologous recombination DNA repair and enhanced sensitivity to DNA damage in prostate cancer cells exposed to anchorage-independence.
abstract: During metastases, cancer cells are temporarily exposed to the condition in which interactions with extracellular environment can be restricted (anchorage-independence). We demonstrate that the sensitivity of prostate cancer cell lines, DU145 and PC-3, to genotoxic treatment (cisplatin and gamma-irradiation) increased several folds when cells were forced to grow in anchorage-independence. This enhanced drug sensitivity was associated with a severe impairment of homologous recombination-directed DNA repair (HRR). The mechanism involves Rad51, which is the major enzymatic component of HRR. The protein level of Rad51 and its recruitment to DNA double-strand breaks (DSBs) were both attenuated. Rad51 deficiency in anchorage-independence was not associated with Rad51 promoter activity, and was not compensated by a constitutive overexpression of Rad51 cDNA. Instead, Rad51 protein level and its ability to colocalize with DSBs were restored in the presence of proteosome inhibitors, or when cells from the suspension cultures were allowed reattachment. Presented results indicate that anchorage-independence sensitizes prostate cancer cells to genotoxic agents; however, it also attenuates faithful component of DNA repair by targeting stability of Rad51. This temporal attenuation of HRR may contribute to the accumulation mutations after DNA damage, and possibly the selection of new adaptations in cells, which survived genotoxic treatment.
authors.affiliation: 1Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 North 12th Street, Biology Life Science Building, Philadelphia, PA 19122, USA.
authors.forename: Jin Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Thu
authors.initials: T
authors.lastname: Ho
authors.forename: Joanna
authors.initials: J
authors.lastname: Trojanek
authors.forename: Janaki
authors.initials: J
authors.lastname: Chintapalli
authors.forename: Maja
authors.initials: M
authors.lastname: Grabacka
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Fernando U
authors.initials: FU
authors.lastname: Garcia
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051135:Rad51 Recombinase; D011995:Recombination, Genetic
chemical_list: D004268:DNA-Binding Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase