Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids
Identifieur interne : 000F45 ( Main/Exploration ); précédent : 000F44; suivant : 000F46Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids
Auteurs : Laure-Anais Vincent [France] ; Chaker Attaoua [France] ; Michel Bellis [France] ; Lucie Rozkydalova [France, République tchèque] ; Kamel Hadj-Kaddour [France] ; Laurence Vian [France] ; Pierre Cuq [France]Source :
- Fundamental & Clinical Pharmacology [ 0767-3981 ] ; 2015-04.
Abstract
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 (VAs) using VA‐resistant MM cell lines (CAL1R‐VCR, CAL1R‐VDS, and CAL1R‐VRB), established by long‐term continuous exposure of parental CAL1‐wt cells to vincristine (VCR), vindesine (VDS), or vinorelbine (VRB), respectively. Transcriptomic profiling using rma and rdam methods led to distinguish two cell groups: CAL1R‐VCR and CAL1R‐VDS, CAL1R‐VRB, and CAL1‐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 CAL1R‐VCR and CAL1R‐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 (CAL1R‐VCR and CAL1R‐VDS, CAL1‐wt and CAL1R‐VRB) could be distinguished regarding the VA‐mediated changes on mean size areas and on acidic compartment volumes. These two parameters were reduced in CAL1R‐VCR and CAL1R‐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 VAs.
Url:
DOI: 10.1111/fcp.12098
Affiliations:
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unit="issue">2</biblScope><biblScope unit="page" from="164">164</biblScope><biblScope unit="page" to="177">177</biblScope><biblScope unit="page-count">14</biblScope><date type="published" when="2015-04">2015-04</date></imprint><idno type="ISSN">0767-3981</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0767-3981</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">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 (VAs) using VA‐resistant MM cell lines (CAL1R‐VCR, CAL1R‐VDS, and CAL1R‐VRB), established by long‐term continuous exposure of parental CAL1‐wt cells to vincristine (VCR), vindesine (VDS), or vinorelbine (VRB), respectively. Transcriptomic profiling using rma and rdam methods led to distinguish two cell groups: CAL1R‐VCR and CAL1R‐VDS, CAL1R‐VRB, and CAL1‐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 CAL1R‐VCR and CAL1R‐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 (CAL1R‐VCR and CAL1R‐VDS, CAL1‐wt and CAL1R‐VRB) could be distinguished regarding the VA‐mediated changes on mean size areas and on acidic compartment volumes. These two parameters were reduced in CAL1R‐VCR and CAL1R‐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 VAs.</div></front></TEI><affiliations><list><country><li>France</li><li>République tchèque</li></country><region><li>Languedoc-Roussillon</li><li>Occitanie (région administrative)</li></region><settlement><li>Montpellier</li></settlement></list><tree><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Vincent, Laure Nais" sort="Vincent, Laure Nais" uniqKey="Vincent L" first="Laure-Anais" last="Vincent">Laure-Anais Vincent</name></region><name sortKey="Attaoua, Chaker" sort="Attaoua, Chaker" uniqKey="Attaoua C" first="Chaker" last="Attaoua">Chaker Attaoua</name><name sortKey="Bellis, Michel" sort="Bellis, Michel" uniqKey="Bellis M" first="Michel" last="Bellis">Michel Bellis</name><name sortKey="Cuq, Pierre" sort="Cuq, Pierre" uniqKey="Cuq P" first="Pierre" last="Cuq">Pierre Cuq</name><name sortKey="Cuq, Pierre" sort="Cuq, Pierre" uniqKey="Cuq P" first="Pierre" last="Cuq">Pierre Cuq</name><name sortKey="Hadj Addour, Kamel" sort="Hadj Addour, Kamel" uniqKey="Hadj Addour K" first="Kamel" last="Hadj-Kaddour">Kamel Hadj-Kaddour</name><name sortKey="Rozkydalova, Lucie" sort="Rozkydalova, Lucie" uniqKey="Rozkydalova L" first="Lucie" last="Rozkydalova">Lucie Rozkydalova</name><name sortKey="Vian, Laurence" sort="Vian, Laurence" uniqKey="Vian L" first="Laurence" last="Vian">Laurence Vian</name></country><country name="République tchèque"><noRegion><name sortKey="Rozkydalova, Lucie" sort="Rozkydalova, Lucie" uniqKey="Rozkydalova L" first="Lucie" last="Rozkydalova">Lucie Rozkydalova</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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