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Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids
Author(s) -
Vincent LaureAnais,
Attaoua Chaker,
Bellis Michel,
Rozkydalova Lucie,
HadjKaddour Kamel,
Vian Laurence,
Cuq Pierre
Publication year - 2015
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12098
Subject(s) - vinca , endoplasmic reticulum , vacuole , unfolded protein response , microbiology and biotechnology , cell culture , biology , cytoplasm , chemistry , pharmacology , genetics
On account of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma ( MM ) remains a therapeutic challenge. This study focuses on acquired resistance to vinca alkaloids ( VA s) using VA ‐resistant MM cell lines ( CAL 1 R ‐ VCR , CAL 1 R ‐ VDS , and CAL 1 R ‐ VRB ), established by long‐term continuous exposure of parental CAL 1‐wt cells to vincristine ( VCR ), vindesine ( VDS ), or vinorelbine ( VRB ), respectively. Transcriptomic profiling using rma and rdam methods led to distinguish two cell groups: CAL 1 R ‐ VCR and CAL 1R‐ VDS , CAL 1 R ‐ VRB , and CAL 1‐wt. mgsa of the specifically altered genes in the first group evidenced the GO terms ‘lysosomal lumen’ and ‘vacuolar lumen’ linked to underexpressed genes, and ‘endoplasmic reticulum ( ER ) stress response’ associated with overexpressed genes. A specific reduction of lysosomal enzymes, independent of acidic vacuole organelle ( AVO ) turnover, was observed ( LTG probe) in CAL 1 R ‐ VCR and CAL 1 R ‐ VDS cells. It was associated with the specific lowering of cathepsin B and L , known to be involved in the lysosomal pathway of apoptosis. Confirming gene profiling, the same groups ( CAL 1 R ‐ VCR and CAL 1 R ‐ VDS , CAL 1‐wt and CAL 1 R ‐ VRB ) could be distinguished regarding the VA ‐mediated changes on mean size areas and on acidic compartment volumes. These two parameters were reduced in CAL 1 R ‐ VCR and CAL 1 R ‐ VDS cells, suggesting a smaller AVO accumulation and thus a reduced sensitivity to lysosomal membrane permeabilization‐mediated apoptosis. In addition, ‘ ER stress response’ inhibition by tauroursodeoxycholic acid induced a higher VA sensitization of the first cell group. In conclusion, lysosomes and unfolded protein response could be key determinants of the differential resistance of MM to VA s.