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

Eduardo Silva-Pavez, Paulina Villar, César Trigo, Esteban Caamaño, Ignacio Niechi, Pablo Pérez, Juan P. Muñoz, Francisco Aguayo, Verónica A. Burzio, Manuel Varas-Godoy, Ariel F. Castro, María I. Colombo, Julio C. Tapia

Resultado de la investigación: Article

1 Cita (Scopus)

Resumen

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.

Idioma originalEnglish
Número de artículo73
PublicaciónCell Death and Disease
Volumen10
N.º2
DOI
EstadoPublished - 25 ene 2019

Huella dactilar

Colorectal Neoplasms
Cell Death
Autophagy
Vacuoles
Cell Survival
Cell Proliferation
Apoptosis
Casein Kinase II
Cholangiocarcinoma
Therapeutic Uses
Multiple Myeloma
Pancreatic Neoplasms
Phosphatidylinositol 3-Kinases
Non-Small Cell Lung Carcinoma
Neoplasms
Carcinogenesis
Phosphotransferases
mechanistic target of rapamycin complex 1
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Citar esto

Silva-Pavez, Eduardo ; Villar, Paulina ; Trigo, César ; Caamaño, Esteban ; Niechi, Ignacio ; Pérez, Pablo ; Muñoz, Juan P. ; Aguayo, Francisco ; Burzio, Verónica A. ; Varas-Godoy, Manuel ; Castro, Ariel F. ; Colombo, María I. ; Tapia, Julio C. / CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. En: Cell Death and Disease. 2019 ; Vol. 10, N.º 2.
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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 Paulina Villar and C{\'e}sar Trigo and Esteban Caama{\~n}o and Ignacio Niechi and Pablo P{\'e}rez and Mu{\~n}oz, {Juan P.} and Francisco Aguayo and Burzio, {Ver{\'o}nica A.} and Manuel Varas-Godoy and Castro, {Ariel F.} and Colombo, {Mar{\'i}a I.} and Tapia, {Julio C.}",
year = "2019",
month = "1",
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doi = "10.1038/s41419-019-1306-x",
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Silva-Pavez, E, Villar, P, Trigo, C, Caamaño, E, Niechi, I, Pérez, P, Muñoz, JP, Aguayo, F, Burzio, VA, Varas-Godoy, M, Castro, AF, Colombo, MI & Tapia, JC 2019, 'CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells', Cell Death and Disease, vol. 10, n.º 2, 73. https://doi.org/10.1038/s41419-019-1306-x

CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. / Silva-Pavez, Eduardo; Villar, Paulina; Trigo, César; Caamaño, Esteban; Niechi, Ignacio; Pérez, Pablo; Muñoz, Juan P.; Aguayo, Francisco; Burzio, Verónica A.; Varas-Godoy, Manuel; Castro, Ariel F.; Colombo, María I.; Tapia, Julio C.

En: Cell Death and Disease, Vol. 10, N.º 2, 73, 25.01.2019.

Resultado de la investigación: Article

TY - JOUR

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

AU - Silva-Pavez, Eduardo

AU - Villar, Paulina

AU - Trigo, César

AU - Caamaño, Esteban

AU - Niechi, Ignacio

AU - Pérez, Pablo

AU - Muñoz, Juan P.

AU - Aguayo, Francisco

AU - Burzio, Verónica A.

AU - Varas-Godoy, Manuel

AU - Castro, Ariel F.

AU - Colombo, María I.

AU - Tapia, Julio C.

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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