Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/2/651 |
| _version_ | 1797413079614488576 |
|---|---|
| author | Pablo Cruz Ulises Ahumada-Castro Galdo Bustos Jordi Molgó Daniela Sauma Alenka Lovy César Cárdenas |
| author_facet | Pablo Cruz Ulises Ahumada-Castro Galdo Bustos Jordi Molgó Daniela Sauma Alenka Lovy César Cárdenas |
| author_sort | Pablo Cruz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:12:23Z |
| format | Article |
| id | doaj.art-d888ea1ab06f4bc7b9bd6464eaa09fd9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:12:23Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d888ea1ab06f4bc7b9bd6464eaa09fd92023-12-03T12:48:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122265110.3390/ijms22020651Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia CellsPablo Cruz0Ulises Ahumada-Castro1Galdo Bustos2Jordi Molgó3Daniela Sauma4Alenka Lovy5César Cárdenas6Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, ChileCenter for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, ChileCenter for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, ChileDépartement 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, FranceBiology Department, Faculty of Science, Universidad de Chile, Santiago 8330015, ChileCenter for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, ChileCenter for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, ChileT-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.https://www.mdpi.com/1422-0067/22/2/651calciumcancermetabolismbioenergeticsT-ALL |
| spellingShingle | Pablo Cruz Ulises Ahumada-Castro Galdo Bustos Jordi Molgó Daniela Sauma Alenka Lovy César Cárdenas 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 calcium cancer metabolism bioenergetics T-ALL |
| title | Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells |
| title_full | Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells |
| title_fullStr | Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells |
| title_full_unstemmed | Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells |
| title_short | Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells |
| title_sort | inhibition of insp3r with xestospongin b reduces mitochondrial respiration and induces selective cell death in t cell acute lymphoblastic leukemia cells |
| topic | calcium cancer metabolism bioenergetics T-ALL |
| url | https://www.mdpi.com/1422-0067/22/2/651 |
| work_keys_str_mv | AT pablocruz inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT ulisesahumadacastro inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT galdobustos inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT jordimolgo inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT danielasauma inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT alenkalovy inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells AT cesarcardenas inhibitionofinsp3rwithxestosponginbreducesmitochondrialrespirationandinducesselectivecelldeathintcellacutelymphoblasticleukemiacells |