Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells

International Journal of Molecular Sciences

Daniela Sauma¹  Ulises Ahumada-Castro²  César Cárdenas²  Pablo Cruz²  Alenka Lovy²  Galdo Bustos²  Jordi Molgó³ 

[1] Biology Department, Faculty of Science, Universidad de Chile, Santiago 8330015, Chile;Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile;Département Médicaments et Technologies pour la Santé, Service d’Ingénierie Moléculaire pour la Santé (SIMoS), ERL CNRS n° 9004, Institut des Sciences du Vivant Frédéric Joliot, CEA, Université Paris-Saclay, bâtiment 152, Point courrier 24, F-91191 Gif sur Yvette, France;

关键词: calcium;    cancer;    metabolism;    bioenergetics;    T-ALL;   

DOI  :  10.3390/ijms22020651

来源: DOAJ

【 摘 要 】

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL.

【 授权许可】

Unknown