LIMK2 Mediates Resistance to Chemotherapeutic Drugs in Neuroblastoma Cells through Regulation of Drug-Induced Cell Cycle Arrest

被引:19
作者
Gamell, Cristina [1 ]
Schofield, Alice V. [1 ,2 ]
Suryadinata, Randy [3 ]
Sarcevic, Boris [2 ,3 ]
Bernard, Ora [1 ,2 ]
机构
[1] St Vincents Inst Med Res, Cytoskeleton & Canc Unit, Melbourne, Vic, Australia
[2] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic, Australia
[3] St Vincents Inst Med Res, Cell Cycle & Canc Unit, Melbourne, Vic, Australia
基金
英国医学研究理事会;
关键词
MULTIDRUG-RESISTANCE; ACTIN DYNAMICS; COFILIN PHOSPHORYLATION; GENE-EXPRESSION; TUBULIN; KINASE; MICROTUBULES; P53; INCREASES; PROTEIN;
D O I
10.1371/journal.pone.0072850
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:13
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