TY - JOUR
T1 - Inhibition of HIF1α-dependent upregulation of phospho-L-Plastin resensitizes multiple myeloma cells to frontline therapy
AU - Bosseler, Manon
AU - Marani, Vanessa
AU - Broukou, Angelina
AU - Lequeux, Amandine
AU - Kaoma, Tony
AU - Schlesser, Vincent
AU - François, Jean Hugues
AU - Palissot, Valérie
AU - Berchem, Guy J.
AU - Aouali, Nasséra
AU - Janji, Bassam
N1 - Funding Information:
This study was supported by Ministère de l’Enseignement Supérieur et de la Recherche (Grant# 20071005), Télévie funding (7.4662.15; 7.4653.14) and Celgen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript. We are thankful to Konrad Pazdrak from the department of Biochemistry and Molecular Biology of University of Texas Medical Branch at Galveston, UTMB for the gift of Phospho-L-Plastin antibody. We are also grateful to Yannick Arlot from the department of “Bases moléculaires de la tumorigenèse: maladie de VHL” from Institute de génétique et development de Rennes for the gift of VHL antibody
Funding Information:
Funding: This study was supported by Ministère de l’Enseignement Supérieur et de la Recherche (Grant# 20071005), Télévie funding (7.4662.15; 7.4653.14) and Celgen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Drug resistance
KW - HIF1α
KW - IMiDs
KW - L-Plastin
KW - MM
KW - PIs
UR - http://www.scopus.com/inward/record.url?scp=85047533019&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/29882856
U2 - 10.3390/ijms19061551
DO - 10.3390/ijms19061551
M3 - Article
C2 - 29882856
AN - SCOPUS:85047533019
SN - 1661-6596
VL - 19
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 6
M1 - 1551
ER -