Inhibition of HIF1α-Dependent Upregulation of Phospho-l-Plastin Resensitizes Multiple Myeloma Cells to Frontline Therapy.
Int J Mol Sci
; 19(6)2018 05 23.
Article
em En
| MEDLINE
| ID: mdl-29882856
ABSTRACT
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR in MM, we established a resistant cell line (MOLP8/R). The exploration of DR mechanisms yielded an overexpression of HIF1α, due to impaired proteasome activity of MOLP8/R. We show that MOLP8/R, like other tumor cells, overexpressing HIF1α, have an increased resistance to the immune system. By exploring the main target genes regulated by HIF1α, we could not show an overexpression of these targets in MOLP8/R. We, however, show that MOLP8/R cells display a very high overexpression of LCP1 gene (l-Plastin) controlled by HIF1α, and that this overexpression also exists in MM patient samples. The l-Plastin activity is controlled by its phosphorylation in Ser5. We further show that the inhibition of l-Plastin phosphorylation restores the sensitivity of MOLP8/R to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Our results reveal a new target gene of DR, controlled by HIF1α.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Regulação para Cima
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Proteínas dos Microfilamentos
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Mieloma Múltiplo
Limite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Luxemburgo