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

Eduardo Silva-Pavez; Ignacio Niechi; Juan P. Muñoz; Francisco Aguayo; Julio C. Tapia; y otros autores.

doi:10.1038/s41419-019-1306-x

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

Título traducido de la contribución: La inhibición de CK2 con silmitasertib promueve la muerte celular similar a la metuosis asociada a la vacuolización masiva catastrófica de las células del cáncer colorrectal.

Eduardo Silva-Pavez
, Ignacio Niechi
, Juan P. Muñoz
, Francisco Aguayo
, Julio C. Tapia
, y otros autores.

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

54 Citas (Scopus)

Resumen

La proteína quinasa CK2 es una Ser/Thr-quinasa altamente conservada y constitutivamente activa que fosforila una gran cantidad de sustratos, lo que resulta en un aumento de la proliferación y supervivencia celular. Un objetivo conocido de CK2 es Akt, un jugador en la vía de señalización PI3K/Akt/mTORC1, que se activa de forma aberrante en el 32% de los pacientes con cáncer colorrectal (CCR). Por otro lado, mTORC1 desempeña un papel importante en la regulación de la síntesis de proteínas, el crecimiento celular y la autofagia. Algunos estudios sugieren que CK2 regula mTORC1 en varios tipos de cáncer. El inhibidor de CK2 desarrollado más recientemente, silmitasertib (anteriormente CX-4945), se ha probado en ensayos de fase I/II para colangiocarcinoma y mieloma múltiple. Se ha demostrado que este fármaco induce la autofagia y mejora la apoptosis en células de cáncer de páncreas y promueve la apoptosis en células de cáncer de pulmón de células no pequeñas. Sin embargo, no se ha probado en estudios para pacientes con CCR. En este trabajo, demostramos que la inhibición de CK2 con silmitasertib disminuye la tumorigénesis in vitro de células de CCR en respuesta a la detención de G2/M, lo cual se correlaciona con la inhibición de mTORC1 y la formación de grandes vacuolas citoplasmáticas. Cabe destacar que los marcadores moleculares indican que estas vacuolas se derivan de una macropinocitosis masiva. En conjunto, estos hallazgos sugieren que una expresión/actividad aberrantemente elevada de CK2 podría desempeñar un papel clave en el CCR, promoviendo la viabilidad y proliferación celular en células no tratadas. Sin embargo, su inhibición con silmitasertib promueve la muerte celular similar a la metuosis, asociada a una vacuolización catastrófica masiva, lo que explica la disminución de la tumorigénesis en etapas posteriores. Estas características de silmitasertib respaldan su posible uso terapéutico en pacientes con CCR y probablemente en otros cánceres dependientes de CK2.

Título traducido de la contribución	La inhibición de CK2 con silmitasertib promueve la muerte celular similar a la metuosis asociada a la vacuolización masiva catastrófica de las células del cáncer colorrectal.
Idioma original	Inglés
Número de artículo	73
Publicación	Cell Death and Disease
Volumen	10
N.º	2
DOI	https://doi.org/10.1038/s41419-019-1306-x
Estado	Publicada - 25 ene. 2019
Publicado de forma externa	Sí

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title = "CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells.",

abstract = "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.",

author = "Eduardo Silva-Pavez and Ignacio Niechi and Mu{\~n}oz, \{Juan P.\} and Francisco Aguayo and Tapia, \{Julio C.\} and \{and other authors.\}",

year = "2019",

month = jan,

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doi = "10.1038/s41419-019-1306-x",

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T1 - CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells.

AU - Silva-Pavez, Eduardo

AU - Niechi, Ignacio

AU - Muñoz, Juan P.

AU - Aguayo, Francisco

AU - Tapia, Julio C.

AU - and other authors.

PY - 2019/1/25

Y1 - 2019/1/25

N2 - 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.

AB - 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.

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

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