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• W1966888959 endingPage "1937" @default.
• W1966888959 startingPage "1928" @default.
• W1966888959 abstract "Lysyl oxidase (LOX) is a multifunctional protein required for normal collagen and elastin biosynthesis and maturation. In addition, LOX has complex roles in cancer in which the lysyl oxidase propeptide (LOX-PP) domain of secreted pro-LOX has tumor-suppressor activity, while the active enzyme promotes metastasis. In prostate cancer cell lines, recombinant LOX-PP (rLOX-PP) inhibits the growth of PC3 cells in vitro by mechanisms that were not characterized, while in DU145 cells rLOX-PP targeted fibroblast growth factor signaling. Because rLOX-PP can enhance effects of a genotoxic chemotherapeutic on breast cancer cell apoptosis, we reasoned that rLOX-PP could target DNA repair pathways typically elevated in cancer. Here we demonstrate for the first time that rLOX-PP inhibits prostate xenograft growth in vivo and that activating phosphorylations of the key DNA repair molecules ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) are inhibited by rLOX-PP expression in vivo. In addition, in vitro studies showed that rLOX-PP inhibits radiation-induced activating phosphorylations of ATM and CHK2 and that exogenously added rLOX-PP protein can localize to the nucleus in both DU145 and PC3 cells. rLOX-PP pull-down studies resulted in detection of a protein complex with the nuclear DNA repair regulator MRE11 in both cell lines, and rLOX-PP localized to radiation-induced nuclear DNA repair foci. Finally, rLOX-PP was shown to sensitize both DU145 and PC3 cells to radiation-induced cell death determined in colony-formation assays. These data provide evidence that rLOX-PP has a nuclear mechanism of action in which it directly interacts with DNA repair proteins to sensitize prostate cancer cells to the effects of ionizing radiation." @default.
• W1966888959 created "2016-06-24" @default.
• W1966888959 creator A5046239953 @default.
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• W1966888959 date "2014-06-02" @default.
• W1966888959 modified "2023-09-27" @default.
• W1966888959 title "Effects of tumor-suppressor lysyl oxidase propeptide on prostate cancer xenograft growth and its direct interactions with DNA repair pathways" @default.
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• W1966888959 doi "https://doi.org/10.1038/onc.2014.147" @default.
• W1966888959 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4254378" @default.
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