Inhibition of HIF1α-Dependent Upregulation of Phospho-l-Plastin Resensitizes Multiple Myeloma Cells to Frontline Therapy
| Autor: | Angelina Broukou, Vincent Schlesser, Manon Bosseler, Amandine Lequeux, Bassam Janji, Nassera Aouali, Guy Berchem, Tony Kaoma, Jean-Hugues François, Vanessa Marani, Valérie Palissot |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic Drug resistance 0302 clinical medicine PIs Phosphorylation HIF1α IMiDs Spectroscopy Multiple myeloma Membrane Glycoproteins medicine.diagnostic_test biology Chemistry drug resistance MM Microfilament Proteins General Medicine Cell Hypoxia Computer Science Applications Up-Regulation Killer Cells Natural 030220 oncology & carcinogenesis Multiple Myeloma Proteasome Endopeptidase Complex Proteolysis Antineoplastic Agents Catalysis Article Inorganic Chemistry 03 medical and health sciences Immune system Downregulation and upregulation Cell Line Tumor medicine Humans Immunologic Factors Physical and Theoretical Chemistry Molecular Biology Organic Chemistry medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Membrane glycoproteins 030104 developmental biology Proteasome l-Plastin Drug Resistance Neoplasm biology.protein Cancer research |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 19; Issue 6; Pages: 1551 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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