Inhibition of HIF1α-dependent upregulation of phospho-L-Plastin resensitizes multiple myeloma cells to frontline therapy

Manon Bosseler, Vanessa Marani, Angelina Broukou, Amandine Lequeux, Tony Kaoma, Vincent Schlesser, Jean Hugues François, Valérie Palissot, Guy J. Berchem, Nasséra Aouali, Bassam Janji*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Article number1551
JournalInternational Journal of Molecular Sciences
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Drug resistance
  • HIF1α
  • IMiDs
  • L-Plastin
  • MM
  • PIs

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