title: The small heat shock protein B8 (HSPB8) confers resistance to bortezomib by promoting autophagic removal of misfolded proteins in multiple myeloma cells.
abstract: Velcade is one of the inescapable drug to treat patient suffering from multiple myeloma (MM) and resistance to this drug represents a major drawback for patients. However, the mechanisms underlying velcade resistance remain incompletely understood. We derived several U266 MM cell clones that resist to velcade. U266-resistant cells were resistant to velcade-induced cell death but exhibited a similar sensitivity to various proapoptotic stimuli. Careful analysis of proteosomal subunits and proteasome enzymatic activities showed that neither the composition nor the activity of the proteasome was affected in velcade-resistant cells. Elimination of velcade-induced poly-ubiquitinated proteins and protein aggregates was drastically stimulated in the resistant cells and correlated with increased cell survival. Inhibition of the lysosomal activity in velcade-resistant cells resulted in an increase of cell aggregates and decrease survival, indicating that aggregates are eliminated through lysosomal degradation. In addition, pangenomic profiling of velcade-sensitive and resistant cells showed that the small heat shock protein HSPB8 was overexpressed in resistant cells. Finally, gain and loss of function experiment demonstrated that HSPB8 is a key factor for velcade resistance. In conclusion, HSPB8 plays an important role for the elimination of aggregates in velcade-resistant cells that contributes to their enhanced survival.
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Mohamed-Amine
authors: MA
authors: Hamouda
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Nathalie
authors: N
authors: Belhacene
authors: Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, USA.
authors: Alexandre
authors: A
authors: Puissant
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Pascal
authors: P
authors: Colosetti
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Guillaume
authors: G
authors: Robert
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Arnaud
authors: A
authors: Jacquel
authors: UMR7275 CNRS-UNS, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
authors: Bernard
authors: B
authors: Mari
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer; These authors contributed equally to this work.
authors: Patrick
authors: P
authors: Auberger
authors: INSERM U1065, C3M, Team 2, Nice, France; Université de Nice Sophia-Antipolis; Equipe labellisée par la Ligue Nationale Contre le Cancer.
authors: Frederic
authors: F
authors: Luciano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000069286:Bortezomib; D017346:Protein Serine-Threonine Kinases