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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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
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/17554
network_acronym_str ES
network_name_str España
repository_id_str
spelling mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.Brandt, MartaGrazioso, Tatiana PFawal, Mohamad-AliTummala, Krishna STorres-Ruiz, RaulRodriguez Perales, SandraPerna, CristianDjouder, NabilAdenomaAdenomatous Polyposis Coli ProteinCarcinogenesisCell ProliferationChromosomal InstabilityColitisColorectal NeoplasmsDNA DamageFemaleHCT116 CellsHomeostasisHumansInflammationInflammatory Bowel DiseasesInterleukin-6IntestinesMaleMechanistic Target of Rapamycin Complex 1Nuclear ProteinsRNA-Binding ProteinsRegenerationSignal TransductionTumor Suppressor Protein p53Dietary 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.Cell PressFundación La CaixaMinisterio de Ciencia y Competitividad (España)Olga Torres Foundation (FOT)European Union (EU)20242024-02-0820182018-01-0920182018-01-09journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/17554reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/175542026-06-12T12:43:37Z
dc.title.none.fl_str_mv mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
title mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
spellingShingle mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
Brandt, Marta
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
title_short mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
title_full mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
title_fullStr mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
title_full_unstemmed mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
title_sort mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis.
dc.creator.none.fl_str_mv Brandt, Marta
Grazioso, Tatiana P
Fawal, Mohamad-Ali
Tummala, Krishna S
Torres-Ruiz, Raul
Rodriguez Perales, Sandra
Perna, Cristian
Djouder, Nabil
author Brandt, Marta
author_facet Brandt, Marta
Grazioso, Tatiana P
Fawal, Mohamad-Ali
Tummala, Krishna S
Torres-Ruiz, Raul
Rodriguez Perales, Sandra
Perna, Cristian
Djouder, Nabil
author_role author
author2 Grazioso, Tatiana P
Fawal, Mohamad-Ali
Tummala, Krishna S
Torres-Ruiz, Raul
Rodriguez Perales, Sandra
Perna, Cristian
Djouder, Nabil
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación La Caixa
Ministerio de Ciencia y Competitividad (España)
Olga Torres Foundation (FOT)
European Union (EU)
dc.subject.none.fl_str_mv 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
topic 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
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-01-09
2018
2018-01-09
2024
2024-02-08
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17554
url http://hdl.handle.net/20.500.12105/17554
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415479485923328
score 15,81155

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