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Published on: September 10, 2014
Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines
S S Chauhan1, X J Liang, A W Su
1Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20842-4254, USA.
British Journal of Cancer
|April 17, 2003
Summary
Defective endosomal acidification in cancer cells may lead to acquired cisplatin resistance. This impacts drug accumulation and degradation, suggesting a new therapeutic target for multidrug resistance.
Area of Science:
- Cell Biology
- Cancer Research
- Drug Resistance Mechanisms
Background:
- Multidrug resistance (MDR) in cancer, particularly cisplatin resistance (CP-r), is a major clinical challenge.
- Reduced drug accumulation and altered endocytosis are implicated in MDR phenotypes.
- The role of lysosomal function and endosomal acidification in acquired drug resistance remains incompletely understood.
Purpose of the Study:
- To investigate the role of endosomal acidification defects in acquired cisplatin resistance in human KB adenocarcinoma cells.
- To characterize the endocytic and lysosomal processing pathways in cisplatin-resistant (CP-r) cell lines.
- To explore potential cross-resistance mechanisms between cisplatin and other toxins.
Main Methods:
- Isolation and characterization of cisplatin-resistant (KB-CP-r) human adenocarcinoma cell lines.
- Assessment of fluid-phase and receptor-mediated endocytosis using horseradish peroxidase (HRPO), Texas Red dextran, and radiolabeled epidermal growth factor ((125)I-EGF).
- Analysis of lysosomal degradation efficiency and cathepsin L activity.
- Treatment with bafilomycin A(1) to inhibit vacuolar proton pumps and assess phenotypic mimicry.
- Evaluation of cross-resistance to Pseudomonas exotoxin.
Main Results:
- KB-CP-r cells exhibited reduced uptake of HRPO and Texas Red dextran, indicating impaired fluid-phase endocytosis.
- While EGF receptor levels were reduced, EGF uptake kinetics were similar; however, lysosomal degradation of internalized EGF was inefficient in KB-CP-r cells.
- KB-CP-r cells displayed less acidic lysosomes and slower cathepsin L processing.
- Treatment with bafilomycin A(1) mimicked the CP-r phenotype, including reduced drug uptake and impaired EGF degradation.
- KB-CP-r cells showed cross-resistance to Pseudomonas exotoxin, and vice versa.
Conclusions:
- Defective endosomal acidification is a key feature of the acquired cisplatin resistance phenotype in KB cells.
- Impaired lysosomal function and reduced endosomal acidity contribute to reduced intracellular drug accumulation and efficacy.
- Targeting endosomal acidification pathways may offer a novel strategy to overcome cisplatin resistance in cancer therapy.
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