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

Abstract

Filamin-A, also called actin binding protein 280 (ABP-280), cross-links the actin filaments into dynamic orthogonal network to serve as scaffolds in multiple signaling pathways. It has been reported that filamin-A interacts with DNA damage response proteins BRCA1 and BRCA2. Defects of filamin-A impair the repair of DNA double strand breaks (DSBs), resulting in sensitization of cells to ionizing radiation. In this study, we sought to test the hypothesis that filamin-A can be used as a target for cancer chemotherapy and as a biomarker to predict cancer response to therapeutic DNA damage. We found that reduction of filamin-A sensitizes cancer cells to chemotherapy reagents bleomycin and cisplatin, delays the repair of not only DSBs but also single strand breaks (SSBs) and interstrand crosslinks (ICLs), and increases chromosome breaks after the drug treatment. By treating a panel of human melanoma cell lines with variable filamin-A expression, we observed a correlation between expression level of filamin-A protein and drug IC(50). We further inhibited the expression of filamin-A in melanoma cells, and found that this confers an increased sensitivity to bleomycin and cisplatin treatment in a mouse xenograft tumor model. These results suggest that filamin-A plays a role in repair of a variety of DNA damage, that lack of filamin-A is a prognostic marker for a better outcome after DNA damage based treatment, and filamin-A can be inhibited to sensitize filamin-A positive cancer cells to therapeutic DNA damage. Thus filamin-A can be used as a biomarker and a target for DNA damage based cancer therapy.

• Authors: Jingyin Yue, Huimei Lu, Jingmei Liu, Marianne Berwick, Zhiyuan Shen
• Journal: DNA repair (DNA Repair (Amst)) Vol. 11 Issue 2 Pg. 192-200 (Feb 01 2012) ISSN: 1568-7856 [Electronic] Netherlands
• PMID: 22051193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Contractile Proteins
• FLNC protein, human
• Filamins
• Microfilament Proteins
• Bleomycin
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (deficiency, metabolism)
• Bleomycin (pharmacology, therapeutic use)
• Cell Line, Tumor
• Chromosomal Instability (drug effects)
• Cisplatin (pharmacology, therapeutic use)
• Contractile Proteins (deficiency, metabolism)
• DNA Breaks, Single-Stranded (drug effects)
• DNA Damage
• DNA Repair (drug effects)
• Filamins
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, genetics, metabolism, pathology)
• Mice
• Microfilament Proteins (deficiency, metabolism)
• Molecular Targeted Therapy (methods)
• Prognosis
• Xenograft Model Antitumor Assays