Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines
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Discussion
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Implication
Laboratory study demonstrates defective endosomal acidification and impaired endocytosis in human carcinoma cells, indicating altered lysosomal function drives drug resistance.
Key Points
- To identify the cellular mechanisms underlying reduced drug accumulation and multidrug resistance in cisplatin-resistant cancer cells.
- Measured fluid-phase and receptor-mediated endocytosis in human KB adenocarcinoma cisplatin-resistant (KB-CP-r) and sensitive cells using horseradish peroxidase, Texas Red dextran, and radiolabeled EGF.
- Evaluated lysosomal degradation, cathepsin L maturation, and organelle acidification, utilizing the vacuolar proton pump inhibitor bafilomycin A1 and testing cross-resistance to Pseudomonas exotoxin.
- Fluid-phase endocytosis decreased several-fold in KB-CP-r cells, with 40% to 60% of internalized 125I-EGF released undegraded compared to 10% in sensitive cells.
- KB-CP-r cells displayed less acidic lysosomes, delayed cathepsin L processing, and bidirectional cross-resistance with Pseudomonas exotoxin.
- Inhibition of the vacuolar proton pump by bafilomycin A1 replicated the resistant phenotype, reducing uptake of HRPO, 125I-EGF, and 14C-carboplatin.
Cite This Study
Chauhan et al. (2003) studied this question.