Filamin-A as a marker and target for DNA damage based cancer therapy

Yue, Jingyin; Lu, Huimei; Liu, Jingmei; Berwick, Marianne; Shen, Zhiyuan

doi:10.1016/j.dnarep.2011.10.019

Cited by 34 publications

(48 citation statements)

References 44 publications

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“…These studies are in agreement with a model that filamin-A is required for efficient DNA repair through HR and NHEJ 19-21. Since Topo II poisons mainly generate DSBs 6, 8, which can be repaired by HR and NHEJ 24, we speculate that filamin-A deficient cells might also be more sensitive to Topo II poisons than filamin-A proficient cells.…”

Section: Resultssupporting

confidence: 91%

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Prognostic Values of Filamin-A Status for Topoisomerase II Poison Chemotherapy

Yue¹,

Lan²,

Yuan³

et al. 2012

Int. J. Biol. Sci.

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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.

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Section: Resultssupporting

confidence: 91%

“…As shown in previous study, about 40-50% of melanoma and breast tumors are filamin-A positive 19, 21. It is likely that these patients will have better prognosis in terms of response to Topo II poisons based chemotherapy due to higher intracellular drug concentration than filamin-A deficient cancers.…”

Section: Discussionmentioning

confidence: 65%

Prognostic Values of Filamin-A Status for Topoisomerase II Poison Chemotherapy

Yue¹,

Lan²,

Yuan³

et al. 2012

Int. J. Biol. Sci.

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“…An unanticipated role of cytoskeletal proteins such as FLNA in the nucleus has also been suggested by the findings that FLNA interacts with androgen receptor (AR) and suppresses AR transcriptional activity [20] and by a recent report showing that FLNA plays a role in the repair of a variety types of DNA damage and that lack of FLNA increases cell sensitivity to DNA damage-based cancer therapy [21]. Although from our confocal microscopy experiment, we cannot perform a quantitative evaluation of FLNA distribution between nucleus and cytoplasm, it is evident that in DU145 cells, FLNA aggregates are apparently more concentrated in the nuclei, dispersed in the cytoplasm and rarely co-localized with actin filaments, while in DU145R80 cells FLNA appears to be mostly localized in the numerous podosomes and/or invadopodia.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype

et al. 2014

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Proteomic analysis identified differentially expressed proteins between zoledronic acid-resistant and aggressive DU145R80 prostate cancer (PCa) cells and their parental DU145 cells. Ingenuity Pathway Analysis (IPA) showed a strong relationship between the identified proteins within a network associated with cancer and with homogeneous cellular functions prevalently related with regulation of cell organization, movement and consistent with the smaller and reduced cell-cell contact morphology of DU145R80 cells. The identified proteins correlated in publically available human PCa genomic data with increased tumor expression and aggressiveness. DU145R80 exhibit also a clear increase of alpha-v-(αv) integrin, and of urokinase receptor (uPAR), both included within the same network of the identified proteins. Interestingly, the actin-rich structures localized at the cell periphery of DU145R80 cells are rich of Filamin A, one of the identified proteins and uPAR which, in turn, co-localizes with αv-integrin, in podosomes and/or invadopodia. Notably, the invasive feature of DU145R80 may be prevented by blocking anti-αv antibody. Overall, we unveil a signaling network that physically links the interior of the nucleus via the cytoskeleton to the extracellular matrix and that could dictate PCa aggressiveness suggesting novel potential prognostic markers and therapeutic targets for PCa patients.

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“…The procedures to stain for γH2AX and RAD51 foci have been described previously [27]–[29]. 53BP1 and phosphorylated DNA-PKcs foci were visualized by the same procedure except that anti-53BP1 (1∶1,000) primary antibody (Bethyl, Montgomery, TX) and anti-Phospho-DNA-PKcs (T2609) (1∶1,000) primary antibodies (Abcam, Cambridge, MA) were used.…”

Section: Methodsmentioning

confidence: 99%

Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome

Yue¹,

Lu²,

Lan³

et al. 2013

PLoS ONE

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Dubowitz Syndrome is an autosomal recessive disorder with a unique set of clinical features including microcephaly and susceptibility to tumor formation. Although more than 140 cases of Dubowitz syndrome have been reported since 1965, the genetic defects of this disease has not been identified. In this study, we systematically analyzed the DNA damage response and repair capability of fibroblasts established from a Dubowitz Syndrome patient. Dubowitz syndrome fibroblasts are hypersensitive to ionizing radiation, bleomycin, and doxorubicin. However, they have relatively normal sensitivities to mitomycin-C, cisplatin, and camptothecin. Dubowitz syndrome fibroblasts also have normal DNA damage signaling and cell cycle checkpoint activations after DNA damage. These data implicate a defect in repair of DNA double strand break (DSB) likely due to defective non-homologous end joining (NHEJ). We further sequenced several genes involved in NHEJ, and identified a pair of novel compound mutations in the DNA Ligase IV gene. Furthermore, expression of wild type DNA ligase IV completely complement the DNA repair defects in Dubowitz syndrome fibroblasts, suggesting that the DNA ligase IV mutation is solely responsible for the DNA repair defects. These data suggests that at least subset of Dubowitz syndrome can be attributed to DNA ligase IV mutations.

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Filamin-A as a marker and target for DNA damage based cancer therapy

Cited by 34 publications

References 44 publications

Prognostic Values of Filamin-A Status for Topoisomerase II Poison Chemotherapy

Prognostic Values of Filamin-A Status for Topoisomerase II Poison Chemotherapy

Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype

Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome

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