The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells

Giovanni Di Maira; Alessandra Gentilini; Mirella Pastore; Alessandra Caligiuri; Benedetta Piombanti; Chiara Raggi; Elisabetta Rovida; Monika Lewinska; Jesper B Andersen; Christian Borgo; Mauro Salvi; Daniele Ottaviani; Maria Ruzzene; Fabio Marra

doi:10.1038/s41389-019-0171-x

The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells

Giovanni Di Maira, Alessandra Gentilini, Mirella Pastore, Alessandra Caligiuri, Benedetta Piombanti, Chiara Raggi, Elisabetta Rovida, Monika Lewinska, Jesper B Andersen, Christian Borgo, Mauro Salvi, Daniele Ottaviani, Maria Ruzzene, Fabio Marra

9 Citationer (Scopus)

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Abstract

Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α' catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.

Originalsprog	Engelsk
Tidsskrift	Oncogenesis
Vol/bind	8
Udgave nummer	11
Sider (fra-til)	61-72
Antal sider	12
ISSN	2157-9024
DOI	https://doi.org/10.1038/s41389-019-0171-x
Status	Udgivet - 1 nov. 2019

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10.1038/s41389-019-0171-xLicens: CC BY

The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cellsForlagets udgivne version, 1,61 MBLicens: CC BY

Citationsformater

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title = "The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells",

abstract = "Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α' catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.",

author = "{Di Maira}, Giovanni and Alessandra Gentilini and Mirella Pastore and Alessandra Caligiuri and Benedetta Piombanti and Chiara Raggi and Elisabetta Rovida and Monika Lewinska and Andersen, {Jesper B} and Christian Borgo and Mauro Salvi and Daniele Ottaviani and Maria Ruzzene and Fabio Marra",

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doi = "10.1038/s41389-019-0171-x",

language = "English",

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TY - JOUR

T1 - The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells

AU - Di Maira, Giovanni

AU - Gentilini, Alessandra

AU - Pastore, Mirella

AU - Caligiuri, Alessandra

AU - Piombanti, Benedetta

AU - Raggi, Chiara

AU - Rovida, Elisabetta

AU - Lewinska, Monika

AU - Andersen, Jesper B

AU - Borgo, Christian

AU - Salvi, Mauro

AU - Ottaviani, Daniele

AU - Ruzzene, Maria

AU - Marra, Fabio

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α' catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.

AB - Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2α and α' catalytic subunits and of the β regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma.

U2 - 10.1038/s41389-019-0171-x

DO - 10.1038/s41389-019-0171-x

M3 - Journal article

C2 - 31641101

SN - 2157-9024

VL - 8

SP - 61

EP - 72

JO - Oncogenesis

JF - Oncogenesis

IS - 11

ER -

The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells

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