mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.

Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt pro...

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Detalles Bibliográficos
Autores: Brandt, Marta, Grazioso, Tatiana P, Fawal, Mohamad-Ali, Tummala, Krishna S, Torres-Ruiz, Raul, Rodriguez Perales, Sandra, Perna, Cristian, Djouder, Nabil
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17554
Acceso en línea:http://hdl.handle.net/20.500.12105/17554
Access Level:acceso abierto
Palabra clave:Adenoma
Adenomatous Polyposis Coli Protein
Carcinogenesis
Cell Proliferation
Chromosomal Instability
Colitis
Colorectal Neoplasms
DNA Damage
Female
HCT116 Cells
Homeostasis
Humans
Inflammation
Inflammatory Bowel Diseases
Interleukin-6
Intestines
Male
Mechanistic Target of Rapamycin Complex 1
Nuclear Proteins
RNA-Binding Proteins
Regeneration
Signal Transduction
Tumor Suppressor Protein p53
Descripción
Sumario:Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL-6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD-associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor-suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC.

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