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, Nathalie Belhacene, Alexandre Puissant, Pascal Colosetti, Guillaume Robert, Arnaud Jacquel, Bernard Mari, Patrick Auberger, Frederic Luciano
文献索引:Oncotarget 5(15) , 6252-66, (2014)
全文:HTML全文
摘要
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.
相关化合物
相关文献:
2015-02-20
[Oncotarget 6(5) , 2604-14, (2015)]
2014-01-01
[PLoS ONE 9(12) , e116152, (2014)]
2015-05-01
[Biomaterials 51 , 1-11, (2015)]
2015-04-01
[J. Pineal Res. 58(3) , 310-20, (2015)]
2015-04-22
[J. Ethnopharmacol. 164 , 265-72, (2015)]