SF3B1 inhibition disrupts malignancy and prolongs survival in glioblastoma patients through BCL2L1 splicing and mTOR/ß-catenin pathways imbalances.

Autor: Fuentes-Fayos AC; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Pérez-Gómez JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., G-García ME; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Jiménez-Vacas JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Blanco-Acevedo C; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Sánchez-Sánchez R; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; Pathology Service, Reina Sofia University Hospital, 14004, Cordoba, Spain., Solivera J; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; Department of Neurosurgery, Reina Sofia University Hospital, 14004, Cordoba, Spain., Breunig JJ; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.; Center for Neural Sciences in Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA., Gahete MD; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Castaño JP; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain., Luque RM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004, Córdoba, Spain. raul.luque@uco.es.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004, Cordoba, Spain. raul.luque@uco.es.; Reina Sofia University Hospital (HURS), 14004, Cordoba, Spain. raul.luque@uco.es.; CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004, Cordoba, Spain. raul.luque@uco.es.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2022 Jan 27; Vol. 41 (1), pp. 39. Date of Electronic Publication: 2022 Jan 27.
DOI: 10.1186/s13046-022-02241-4
Abstrakt: Background: Glioblastoma is one of the most devastating cancer worldwide based on its locally aggressive behavior and because it cannot be cured by current therapies. Defects in alternative splicing process are frequent in cancer. Recently, we demonstrated that dysregulation of the spliceosome is directly associated with glioma development, progression, and aggressiveness.
Methods: Different human cohorts and a dataset from different glioma mouse models were analyzed to determine the mutation frequency as well as the gene and protein expression levels between tumor and control samples of the splicing-factor-3B-subunit-1 (SF3B1), an essential and druggable spliceosome component. SF3B1 expression was also explored at the single-cell level across all cell subpopulations and transcriptomic programs. The association of SF3B1 expression with relevant clinical data (e.g., overall survival) in different human cohorts was also analyzed. Different functional (proliferation/migration/tumorspheres and colonies formation/VEGF secretion/apoptosis) and mechanistic (gene expression/signaling pathways) assays were performed in three different glioblastomas cell models (human primary cultures and cell lines) in response to SF3B1 blockade (using pladienolide B treatment). Moreover, tumor progression and formation were monitored in response to SF3B1 blockade in two preclinical xenograft glioblastoma mouse models.
Results: Our data provide novel evidence demonstrating that the splicing-factor-3B-subunit-1 (SF3B1, an essential and druggable spliceosome component) is low-frequency mutated in human gliomas (~ 1 %) but widely overexpressed in glioblastoma compared with control samples from the different human cohorts and mouse models included in the present study, wherein SF3B1 levels are associated with key molecular and clinical features (e.g., overall survival, poor prognosis and/or drug resistance). Remarkably, in vitro and in vivo blockade of SF3B1 activity with pladienolide B drastically altered multiple glioblastoma pathophysiological processes (i.e., reduction in proliferation, migration, tumorspheres formation, VEGF secretion, tumor initiation and increased apoptosis) likely by suppressing AKT/mTOR/ß-catenin pathways, and an imbalance of BCL2L1 splicing.
Conclusions: Together, we highlight SF3B1 as a potential diagnostic and prognostic biomarker and an efficient pharmacological target in glioblastoma, offering a clinically relevant opportunity worth to be explored in humans.
(© 2022. The Author(s).)
Databáze: MEDLINE
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