Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas
Abstract The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the syn...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-024-00540-3 |
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| author | Anaís Sánchez-Castillo Kim G. Savelkouls Alessandra Baldini Judith Hounjet Pierre Sonveaux Paulien Verstraete Kim De Keersmaecker Barbara Dewaele Benny Björkblom Beatrice Melin Wendy Y. Wu Rickard L. Sjöberg Kasper M. A. Rouschop Martijn P. G. Broen Marc Vooijs Kim R. Kampen |
| author_facet | Anaís Sánchez-Castillo Kim G. Savelkouls Alessandra Baldini Judith Hounjet Pierre Sonveaux Paulien Verstraete Kim De Keersmaecker Barbara Dewaele Benny Björkblom Beatrice Melin Wendy Y. Wu Rickard L. Sjöberg Kasper M. A. Rouschop Martijn P. G. Broen Marc Vooijs Kim R. Kampen |
| author_sort | Anaís Sánchez-Castillo |
| collection | DOAJ |
| description | Abstract The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients. |
| format | Article |
| id | doaj-art-d61b57eb4ce140da832cf94a49f0efd8 |
| institution | Kabale University |
| issn | 2157-9024 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-d61b57eb4ce140da832cf94a49f0efd82024-11-17T12:49:24ZengNature Publishing GroupOncogenesis2157-90242024-11-0113111810.1038/s41389-024-00540-3Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomasAnaís Sánchez-Castillo0Kim G. Savelkouls1Alessandra Baldini2Judith Hounjet3Pierre Sonveaux4Paulien Verstraete5Kim De Keersmaecker6Barbara Dewaele7Benny Björkblom8Beatrice Melin9Wendy Y. Wu10Rickard L. Sjöberg11Kasper M. A. Rouschop12Martijn P. G. Broen13Marc Vooijs14Kim R. Kampen15Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionPole of Pharmacology, Institut de Recherche Experimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain)Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI)Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI)Center for Human Genetics, Laboratory for Genetics of Malignant Disorders, University Hospitals Leuven and KU LeuvenDepartment of Chemistry, Umeå UniversityDepartment of Diagnostics and Intervention, Oncology, Umeå UniversityDepartment of Diagnostics and Intervention, Oncology, Umeå UniversityDepartment of Clinical Science, Neurosciences, Umeå UniversityDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionDepartment of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical CentreDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionDepartment of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and ReproductionAbstract The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.https://doi.org/10.1038/s41389-024-00540-3 |
| spellingShingle | Anaís Sánchez-Castillo Kim G. Savelkouls Alessandra Baldini Judith Hounjet Pierre Sonveaux Paulien Verstraete Kim De Keersmaecker Barbara Dewaele Benny Björkblom Beatrice Melin Wendy Y. Wu Rickard L. Sjöberg Kasper M. A. Rouschop Martijn P. G. Broen Marc Vooijs Kim R. Kampen Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas Oncogenesis |
| title | Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas |
| title_full | Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas |
| title_fullStr | Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas |
| title_full_unstemmed | Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas |
| title_short | Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas |
| title_sort | sertraline chloroquine combination therapy to target hypoxic and immunosuppressive serine glycine synthesis dependent glioblastomas |
| url | https://doi.org/10.1038/s41389-024-00540-3 |
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