title: Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids.
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.
authors.affiliation: Laboratoire de Toxicologie du Médicament, Institut des Biomolécules Max Mousseron (UMR5247), UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, 15 Avenue Charles Flahault, BP14491, 34093, Montpellier Cedex 05, France.
authors.forename: Laure-Anais
authors.initials: LA
authors.lastname: Vincent
authors.forename: Chaker
authors.initials: C
authors.lastname: Attaoua
authors.forename: Michel
authors.initials: M
authors.lastname: Bellis
authors.forename: Lucie
authors.initials: L
authors.lastname: Rozkydalova
authors.forename: Kamel
authors.initials: K
authors.lastname: Hadj-Kaddour
authors.forename: Laurence
authors.initials: L
authors.lastname: Vian
authors.forename: Pierre
authors.initials: P
authors.lastname: Cuq
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics*; D014748:Vinca Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D014748:Vinca Alkaloids
keywords: lysosomes; melanoma; microarray analysis; neoplasm drug resistance; unfolded protein response; vinca alkaloids