Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma

Autor: Sabrina Eichwald, Christine Müller, René Winkler, Cornelis F. Calkhoven, Zhao-Qi Wang, Christian Kosan, Laura M Zidek, Andreas Krämer, Gertrud Kortman, Joost Kluiver, Anke van den Berg, Iver Petersen, Heiko Schimmel, Carsten Dornblut, Götz Hartleben
Přispěvatelé: Stem Cell Aging Leukemia and Lymphoma (SALL), Translational Immunology Groningen (TRIGR)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
mTORC1
Mice
SCID
MYC
medicine.disease_cause
Tuberous Sclerosis Complex 1 Protein
ACTIVATION
Mice
Mice
Inbred NOD
hemic and lymphatic diseases
RNA
Neoplasm
Burkitt's lymphoma
General Neuroscience
TSC1/2
Articles
MITOCHONDRIAL BIOGENESIS
Burkitt Lymphoma
CANCER
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
MCF-7 Cells
Heterografts
MTORC1 INHIBITOR EVEROLIMUS
STEM-CELLS
Signal Transduction
congenital
hereditary
and neonatal diseases and abnormalities
TRANSLATION INITIATION
Biology
Mechanistic Target of Rapamycin Complex 1
General Biochemistry
Genetics and Molecular Biology
Article
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Tuberous Sclerosis Complex 2 Protein
medicine
C-MYC
TUMORIGENESIS
Animals
Humans
Molecular Biology
Mechanistic target of rapamycin
General Immunology and Microbiology
Cancer
PROTEIN-KINASE
medicine.disease
GENE
Lymphoma
MicroRNAs
030104 developmental biology
HEK293 Cells
Cancer research
biology.protein
TSC1
TSC2
Carcinogenesis
Neoplasm Transplantation
Zdroj: The EMBO journal, 37(21)
The EMBO Journal
The EMBO Journal, 37(21):98589. Wiley
ISSN: 0261-4189
Popis: The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.
Databáze: OpenAIRE
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