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LIMK2 mediates resistance to chemotherapeutic drugs in neuroblastoma cells through regulation of drug-induced cell cycle arrest

Drug resistance is a major obstacle for the successful treatment of many malignancies, including neuroblastoma, the most common extracranial solid tumor in childhood. Therefore, current attempts to improve the survival of neuroblastoma patients, as well as those with other cancers, largely depend on...

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Published in:PloS one 2013-08, Vol.8 (8), p.e72850
Main Authors: Gamell, Cristina, Schofield, Alice V, Suryadinata, Randy, Sarcevic, Boris, Bernard, Ora
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description Drug resistance is a major obstacle for the successful treatment of many malignancies, including neuroblastoma, the most common extracranial solid tumor in childhood. Therefore, current attempts to improve the survival of neuroblastoma patients, as well as those with other cancers, largely depend on strategies to counter cancer cell drug resistance; hence, it is critical to understand the molecular mechanisms that mediate resistance to chemotherapeutics. The levels of LIM-kinase 2 (LIMK2) are increased in neuroblastoma cells selected for their resistance to microtubule-targeted drugs, suggesting that LIMK2 might be a possible target to overcome drug resistance. Here, we report that depletion of LIMK2 sensitizes SHEP neuroblastoma cells to several microtubule-targeted drugs, and that this increased sensitivity correlates with enhanced cell cycle arrest and apoptosis. Furthermore, we show that LIMK2 modulates microtubule acetylation and the levels of tubulin Polymerization Promoting Protein 1 (TPPP1), suggesting that LIMK2 may participate in the mitotic block induced by microtubule-targeted drugs through regulation of the microtubule network. Moreover, LIMK2-depleted cells also show an increased sensitivity to certain DNA-damage agents, suggesting that LIMK2 might act as a general pro-survival factor. Our results highlight the exciting possibility of combining specific LIMK2 inhibitors with anticancer drugs in the treatment of multi-drug resistant cancers.
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subjects Acetylation
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic drugs
Antitumor agents
Apoptosis
Cancer
Cell adhesion & migration
Cell cycle
Cell Cycle - drug effects
Cell Line, Tumor
Chemotherapy
Children
Cytoskeleton
Deoxyribonucleic acid
DNA
DNA Damage
Drug resistance
Drug Resistance, Neoplasm - physiology
Drug therapy
Drugs
Humans
Kinases
LIM kinase
Lim Kinases - physiology
Localization
Medical research
Microtubules - metabolism
Molecular modelling
Multidrug resistance
Nerve Tissue Proteins - metabolism
Neuroblastoma
Neuroblastoma - pathology
Neuroblastoma cells
Neuroblasts
Pediatrics
Phosphorylation
Polymerization
Proteins
Sensitivity
Sensitivity enhancement
Solid tumors
Survival
Survival factor
Tubulin
Up-Regulation - drug effects
title LIMK2 mediates resistance to chemotherapeutic drugs in neuroblastoma cells through regulation of drug-induced cell cycle arrest
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