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内细胞受体蛋白LRP-1调节MCF-7细胞中P-糖蛋白介导的耐药性

Aubery Henry¹, Marine Mauperin¹, Jerome Devy¹

¹UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR SEN, URCA, Reims cedex, France.

|September 28, 2023

概括

低密度脂蛋白受体相关蛋白-1 (LRP-1) 阻塞使多抗药 (MDR) 癌细胞对化疗敏感. LRP-1 调节P-glycoprotein (P-gp) 表达和 lysosomal 贩运,克服了MDR.

科学领域:

癌症研究癌症研究
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

多种药物耐药性 (MDR) 是癌症化疗中的一个重大挑战,通常由像P-glycoprotein (P-gp) 这样的膜运输蛋白介导.
主要在等离子体膜上的P-gp可以被内细胞化,导致其存在于溶酶体中,在那里它将像多克索鲁比 (Dox) 这样的药物隔离起来.
低密度脂蛋白受体相关蛋白-1 (LRP-1) 涉及细胞内和瘤进展,这表明它可能在MDR中发挥作用.

研究的目的:

调查LRP-1在P-gp表达和通过内细胞分裂的亚细胞再分配中的作用.
确定LRP-1对MCF-7细胞中P-gp介导的多药性耐药性的影响.

主要方法:

使用的MCF-7耐药细胞 (MCF-7R) 过度表达P-gp,LRP-1和LAMP-1.
在MCF-7R细胞中分析了溶酶体密度和P-gp定位.
研究了LRP-1阻塞对溶酶体密度,LAMP-1和P-gp水平以及P-gp亚细胞分布的影响.
在LRP-1封锁后评估了多克索鲁比 (Dox) 的核吸收和ERK 1/2激活.

主要成果:

MCF-7R细胞对Dox具有11.66倍的抗性,P-gp,LRP-1和LAMP-1的过度表达.
MCF-7R细胞显示主要是高密度溶解体,P-gp局部存在于血膜和溶解体中.
阻断LRP-1降低了溶酶体密度,LAMP-1和P-gp水平,并改变了P-gp亚细胞分布.
阻止LRP-1恢复了Dox核吸收和ERK 1/2激活,使MCF-7R细胞对Dox.敏感.

结论:

LRP-1调节P-gp的表达和其通过内细胞酶介导的再分配到 lysosomes.
在MCF-7细胞中,LRP-1增强了P-gp获得的多克索鲁比辛耐药性.
准LRP-1是克服癌症治疗中P-gp介导的多药性耐药性的潜在策略.

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