CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells

Autores
Silva Pavez, Eduardo; Villar, Paulina; Trigo, César; Caamaño, Esteban; Niechi, Ignacio; Pérez, Pablo; Muñoz, Juan Pablo; Aguayo, Francisco; Burzio, Verónica A.; Varas Godoy, Manuel; Castro, Ariel F.; Colombo, Maria Isabel; Tapia, Julio C.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
Fil: Silva Pavez, Eduardo. Universidad de Chile; Chile
Fil: Villar, Paulina. Universidad de Chile; Chile
Fil: Trigo, César. Universidad de Chile; Chile
Fil: Caamaño, Esteban. Universidad de Chile; Chile
Fil: Niechi, Ignacio. Universidad de Chile; Chile. Universidad Austral de Chile; Chile
Fil: Pérez, Pablo. Universidad de Chile; Chile
Fil: Muñoz, Juan Pablo. Universidad de Chile; Chile
Fil: Aguayo, Francisco. Universidad de Chile; Chile
Fil: Burzio, Verónica A.. Universidad Andrés Bello; Chile
Fil: Varas Godoy, Manuel. Universidad de Los Andes; Chile
Fil: Castro, Ariel F.. Universidad de Concepción; Chile
Fil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Tapia, Julio C.. Universidad de Chile; Chile
Materia
CANCER
CK2
MTORC1
AUTOPHAGY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/123990
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/123990
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cellsSilva Pavez, EduardoVillar, PaulinaTrigo, CésarCaamaño, EstebanNiechi, IgnacioPérez, PabloMuñoz, Juan PabloAguayo, FranciscoBurzio, Verónica A.Varas Godoy, ManuelCastro, Ariel F.Colombo, Maria IsabelTapia, Julio C.CANCERCK2MTORC1AUTOPHAGYhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.Fil: Silva Pavez, Eduardo. Universidad de Chile; ChileFil: Villar, Paulina. Universidad de Chile; ChileFil: Trigo, César. Universidad de Chile; ChileFil: Caamaño, Esteban. Universidad de Chile; ChileFil: Niechi, Ignacio. Universidad de Chile; Chile. Universidad Austral de Chile; ChileFil: Pérez, Pablo. Universidad de Chile; ChileFil: Muñoz, Juan Pablo. Universidad de Chile; ChileFil: Aguayo, Francisco. Universidad de Chile; ChileFil: Burzio, Verónica A.. Universidad Andrés Bello; ChileFil: Varas Godoy, Manuel. Universidad de Los Andes; ChileFil: Castro, Ariel F.. Universidad de Concepción; ChileFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tapia, Julio C.. Universidad de Chile; ChileNature Publishing Group2019-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/123990Silva Pavez, Eduardo; Villar, Paulina; Trigo, César; Caamaño, Esteban; Niechi, Ignacio; et al.; CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells; Nature Publishing Group; Cell Death and Disease; 10; 2; 2-2019; 1-132041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-019-1306-xinfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-019-1306-xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:15Zoai:ri.conicet.gov.ar:11336/123990instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:49:15.616CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
title CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
spellingShingle CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
Silva Pavez, Eduardo
CANCER
CK2
MTORC1
AUTOPHAGY
title_short CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
title_full CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
title_fullStr CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
title_full_unstemmed CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
title_sort CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells
dc.creator.none.fl_str_mv Silva Pavez, Eduardo
Villar, Paulina
Trigo, César
Caamaño, Esteban
Niechi, Ignacio
Pérez, Pablo
Muñoz, Juan Pablo
Aguayo, Francisco
Burzio, Verónica A.
Varas Godoy, Manuel
Castro, Ariel F.
Colombo, Maria Isabel
Tapia, Julio C.
author Silva Pavez, Eduardo
author_facet Silva Pavez, Eduardo
Villar, Paulina
Trigo, César
Caamaño, Esteban
Niechi, Ignacio
Pérez, Pablo
Muñoz, Juan Pablo
Aguayo, Francisco
Burzio, Verónica A.
Varas Godoy, Manuel
Castro, Ariel F.
Colombo, Maria Isabel
Tapia, Julio C.
author_role author
author2 Villar, Paulina
Trigo, César
Caamaño, Esteban
Niechi, Ignacio
Pérez, Pablo
Muñoz, Juan Pablo
Aguayo, Francisco
Burzio, Verónica A.
Varas Godoy, Manuel
Castro, Ariel F.
Colombo, Maria Isabel
Tapia, Julio C.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CANCER
CK2
MTORC1
AUTOPHAGY
topic CANCER
CK2
MTORC1
AUTOPHAGY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
Fil: Silva Pavez, Eduardo. Universidad de Chile; Chile
Fil: Villar, Paulina. Universidad de Chile; Chile
Fil: Trigo, César. Universidad de Chile; Chile
Fil: Caamaño, Esteban. Universidad de Chile; Chile
Fil: Niechi, Ignacio. Universidad de Chile; Chile. Universidad Austral de Chile; Chile
Fil: Pérez, Pablo. Universidad de Chile; Chile
Fil: Muñoz, Juan Pablo. Universidad de Chile; Chile
Fil: Aguayo, Francisco. Universidad de Chile; Chile
Fil: Burzio, Verónica A.. Universidad Andrés Bello; Chile
Fil: Varas Godoy, Manuel. Universidad de Los Andes; Chile
Fil: Castro, Ariel F.. Universidad de Concepción; Chile
Fil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Tapia, Julio C.. Universidad de Chile; Chile
description Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
publishDate 2019
dc.date.none.fl_str_mv 2019-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/123990
Silva Pavez, Eduardo; Villar, Paulina; Trigo, César; Caamaño, Esteban; Niechi, Ignacio; et al.; CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells; Nature Publishing Group; Cell Death and Disease; 10; 2; 2-2019; 1-13
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/123990
identifier_str_mv Silva Pavez, Eduardo; Villar, Paulina; Trigo, César; Caamaño, Esteban; Niechi, Ignacio; et al.; CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells; Nature Publishing Group; Cell Death and Disease; 10; 2; 2-2019; 1-13
2041-4889
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-019-1306-x
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-019-1306-x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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