title: Prognostic values of filamin-A status for topoisomerase II poison chemotherapy.
abstract: Filamin-A, also called Actin Binding Protein-280, is not only an essential component of the cytoskeleton networks, but also serves as the scaffold in various signaling networks. It has been shown that filamin-A facilitates DNA repair and filamin-A proficient cells are more resistant to ionizing radiation, bleomycin, and cisplatin. In this study, we assessed the role of filamin-A in modulating cancer cell sensitivity to Topo II poisons, including etoposide and doxorubicin. Intriguingly, we found that cells with filamin-A expression are more sensitive to Topo II poisons than those with defective filamin-A, and filamin-A proficient xenograft melanomas have better response to etoposide treatment than the filamin-A deficient tumors. This is associated with more potent induction of DNA double strand breaks (DSBs) by Topo II poisons in filamin-A proficient cells than the deficient cells. Although the expression of filamin-A enables cells a slightly stronger capability to repair DSB, the net outcome is that filamin-A proficient cells bear more DSBs due to the significantly enhanced DSB induction by Topo II poisons in these cells. We further found that filamin-A proficient cells have increased drug influx and decreased drug efflux, suggesting that filamin-A modulates the intra-cellular drug kinetics of Topo II poisons to facilitate the generation of DSB after Topo II poison exposure. These data suggest a novel function of filamin-A in regulating the pharmacokinetics of Topo II poisons, and that the status of filamin-A may be used as a prognostic marker for Topo II poisons based cancer treatments.
authors.affiliation: Department of Radiation Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
authors.forename: Jingyin
authors.initials: J
authors.lastname: Yue
authors.forename: Shijie
authors.initials: S
authors.lastname: Lan
authors.forename: Changji
authors.initials: C
authors.lastname: Yuan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000627:therapeutic use; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D005260:Female; D064448:Filamins; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D011839:Radiation, Ionizing; D059005:Topoisomerase II Inhibitors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins; D059005:Topoisomerase II Inhibitors; D001761:Bleomycin; D002945:Cisplatin