溶体ABCC3、ABCC5和ABCC10的活性负责多柔比星和紫杉醇-Oregongreen488在紫杉醇耐药癌症细胞系中的溶体滞留。

IF 2.5 Q3 CELL BIOLOGY
Karolina Gronkowska, Sylwia Michlewska, Agnieszka Robaszkiewicz
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引用次数: 0

摘要

背景/目的:紫杉醇诱导的癌症细胞多药耐药性导致化疗失败率和疾病复发。已经描述了几种机制,这些机制是观察到的耐药性的基础,包括ABCB1(P-糖蛋白)的过度表达,其代表ATP结合盒(ABC)跨膜蛋白,其在溶酶体膜中的功能发生与这些细胞器中的药物积累有关。方法:利用多药耐药的癌症和癌症非小细胞肺癌细胞系的临床相关模型,我们为ABCC亚家族成员在多药耐药表型的药物溶酶体固存中的作用提供了证据。蛋白质表达水平及其细胞定位使用蛋白质印迹和共聚焦显微镜进行测量。通过共聚焦显微镜和流式细胞术分析药物积聚。用雷沙苏林法和安烯新V碘化丙啶染色法检测药物的细胞毒性。结果:无论基因表达的改变如何,紫杉醇都能诱导ABCC3、ABCC5和ABCC10在细胞内的重新分布,并在溶酶体中富集。ABCC抑制剂的使用和这三个基因的短暂沉默限制了阿霉素和紫杉醇-OregonGreen488在溶酶体中的积累,而对细胞内的总药物水平几乎没有影响。癌症细胞也对不同酸度的各种结构无关的化疗药物敏感。结论:在抗紫杉醇癌症细胞中,溶酶体膜锚定ABCC蛋白,该蛋白保持功能活性,并能够将化疗药物加载到溶酶体中。因此,靶向溶酶体ABCC转运蛋白可能有助于通过减少药物在溶酶体中的积累来克服紫杉醇诱导的耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Activity of Lysosomal ABCC3, ABCC5 and ABCC10 is Responsible for Lysosomal Sequestration of Doxorubicin and Paclitaxel-Oregongreen488 in Paclitaxel-Resistant Cancer Cell Lines.

Background/aims: Cancer cell multidrug resistance induced by paclitaxel contributes to the high failure rates of chemotherapy and relapse of the disease. Several mechanisms have been described that underlie the observed resistance, including the overexpression of ABCB1 (P-glycoprotein), which represents an ATP-binding cassette (ABC) transmembrane protein, and its functional occurrence in lysosomal membranes is linked to drug accumulation in these organelles.

Methods: Using clinically-relevant models of paclitaxel-resistant triple-negative breast cancer and non-small cell lung cancer cell lines, we provide evidence for the role of ABCC subfamily members in the lysosomal sequestration of drugs in multidrug resistant phenotypes. Proteins expression level and its cellular localisation was measured using Western Blot and confocal microscopy. Drug accumulation was analysed by confocal microscopy and flow cytometry. Drug cytotoxicity was tested using resasurin assay and anexin V propidium iodide staining.

Results: Regardless of the alteration in gene expression, paclitaxel induced the intracellular redistribution of ABCC3, ABCC5 and ABCC10 and their enrichment in lysosomes. The use of ABCC inhibitors and transient silencing of these three genes limited the accumulation of doxorubicin and paclitaxel-OregonGreen488 in lysosomes, while having little impact on the total drug level inside cells. The cancer cells were also sensitized to various structurally unrelated chemotherapeutics of differing acidity.

Conclusion: The results suggest that lysosome membranes anchored ABCC proteins which remained functionally active and were capable to load chemotherapeutics into lysosomes in paclitaxel-resistant cancer cells. Therefore, targeting of lysosomal ABCC transporters may help to overcome paclitaxel-induced resistance by reducing the accumulation of drugs in lysosomes.

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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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