ABSTRACT
Although dexamethasone (DEX) remains a first-line agent for multiple myeloma (MM) therapy, the development of DEX resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to DEX. This study demonstrated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) was highly expressed in DEX-resistant myeloma cell lines, and upregulation of NEAT1 was tightly linked to poor prognosis. The in-depth study revealed that during the development of DEX resistance in these cells, the miR-193a levels were decreased, which resulted in the increased expression of the target gene myeloid cell leukemia-1 (MCL1). We also found knockdown of NEAT1, the DEX-induced sensitivity was enhanced in the resistant cells. Meanwhile, overexpression of NEAT1 increased the DEX-induced resistance in the sensitive cells. In conclusion, the NEAT1/miR-193a/MCL1 pathway is closely associated with the development of DEX resistance in myeloma cells, and knockdown of NEAT1 can significantly improve DEX sensitivity in MM.
Subject(s)
Dexamethasone/therapeutic use , Drug Resistance, Neoplasm , MicroRNAs/antagonists & inhibitors , Multiple Myeloma/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , RNA, Long Noncoding/metabolism , Signal Transduction/drug effects , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Dexamethasone/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , MicroRNAs/metabolism , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Mutation , Myeloid Cell Leukemia Sequence 1 Protein/agonists , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasm Staging , Prognosis , RNA/agonists , RNA/antagonists & inhibitors , RNA/metabolism , RNA Interference , RNA, Long Noncoding/agonists , RNA, Long Noncoding/antagonists & inhibitors , RNA, Neoplasm/agonists , RNA, Neoplasm/antagonists & inhibitors , RNA, Neoplasm/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Survival AnalysisABSTRACT
Small molecule S1 is a pan-BH3 mimetic that can bind antiapoptotic Bcl-2, Bcl-xL and Mcl-1 proteins. Herein, different Bcl-2 member expression cancer cell lines (NCI-H345, MCF-7, SMMC-7721 and Hela) and cells deficient in Bax and/or Bak by shRNA were used to unravel the cascade of events by which S1 promotes apoptosis compared with Bcl-2/Bcl-xL inhibitor ABT-737. We identified that S1 exhibited broader antitumour spectrum than ABT-737 through disruption of more Bcl-2 interactions including Mcl-1/Bak interaction. Moreover, the individual and combined roles of Bax and Bak in S1-induced apoptosis were revealed. Our results showed that S1 induced a Bak-mediated apoptosis. Bak played a predominant role in either S1 or ABT-737-induced apoptosis through the cooperation with Bax on the formation of large oligomers on mitochondrial membrane.
