TY - JOUR
T1 - A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis
AU - Chen, Shuang
AU - Zhang, Yu
AU - Zhou, Liang
AU - Leng, Yun
AU - Lin, Hui
AU - Kmieciak, Maciej
AU - Pei, Xin Yan
AU - Jones, Richard
AU - Orlowski, Robert Z.
AU - Dai, Yun
AU - Grant, Steven
N1 - Publisher Copyright:
© 2014 by The American Society of Hematology.
PY - 2014/10/23
Y1 - 2014/10/23
N2 - Bim contributes to resistance to various standard and novel agents. Herewe demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bimhi) in most MM cell lines and primary CD138+ MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bimhi cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/ Bcl-xL, potently killed bortezomib-resistant cells. These events were correlatedwithBimassociated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bimhi cells. In Bimlow cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bimexpression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim-/- mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
AB - Bim contributes to resistance to various standard and novel agents. Herewe demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bimhi) in most MM cell lines and primary CD138+ MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bimhi cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/ Bcl-xL, potently killed bortezomib-resistant cells. These events were correlatedwithBimassociated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bimhi cells. In Bimlow cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bimexpression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim-/- mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
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U2 - 10.1182/blood-2014-03-564534
DO - 10.1182/blood-2014-03-564534
M3 - Article
C2 - 25208888
AN - SCOPUS:84908257452
SN - 0006-4971
VL - 124
SP - 2687
EP - 2697
JO - Blood
JF - Blood
IS - 17
ER -