The small heat shock protein B8 (HSPB8) confers resistance to bortezomib by promoting autophagic removal of misfolded proteins in multiple myeloma cells

// Mohamed-Amine Hamouda 1,2,3 , Nathalie Belhacene 1,2,3 , Alexandre Puissant 4 , Pascal Colosetti 1,2,3 , Guillaume Robert 1,2,3 , Arnaud Jacquel 1,2,3 , Bernard Mari 5 , Patrick Auberger 1,2,3,* and Frederic Luciano 1,2,3,* 1 INSERM U1065, C3M, Team 2, Nice, France 2 Universite de Nice Sophia-Antipolis 3 Equipe labellisee par la Ligue Nationale Contre le Cancer 4 Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, USA 5 UMR7275 CNRS-UNS, Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France * These authors contributed equally to this work Correspondence: Frederic Luciano, email: // Keywords : multiple myeloma, velcade, resistance, HSPB8, aggregates, autophagy Received : May 13, 2014 Accepted : July 8, 2014 Published : July 9, 2014 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.