Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation

Abbas Shakoori; Andrei Ougolkov; Wei Yu Zhi; Bin Zhang; Mohammad H. Modarressi; Daniel D. Billadeau; Masayoshi Mai; Yutaka Takahashi; Toshinari Minamoto

doi:10.1016/j.bbrc.2005.07.041

Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation

Abbas Shakoori, Andrei Ougolkov, Wei Yu Zhi, Bin Zhang, Mohammad H. Modarressi, Daniel D. Billadeau, Masayoshi Mai, Yutaka Takahashi, Toshinari Minamoto^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

Abstract

Glycogen synthase kinase 3β (GSK3β) reportedly has opposing roles, repressing Wnt/β-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-κB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3β in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3β expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of β-catenin oncoprotein in the tumor cells. Inhibition of GSK3β activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3β activity by chemical inhibitors and its expression by RNA interference targeting GSK3β induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3β in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

Original language	English (US)
Pages (from-to)	1365-1373
Number of pages	9
Journal	Biochemical and Biophysical Research Communications
Volume	334
Issue number	4
DOIs	https://doi.org/10.1016/j.bbrc.2005.07.041
State	Published - Sep 9 2005

Funding

We thank Dr. Hiroyasu Esumi (National Cancer Center Research Institute, Japan) for reviewing the manuscript, and Mr. Michael Meyer for editorial assistance. This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture (to T.M.), from the Ministry of Health, Labour and Welfare (to T.M.), and from the Japan Society for the Promotion of Science (to T.M., A.O., and B.Z.).

Keywords

Apoptosis
Cell survival
Colorectal cancer
Glycogen synthase kinase 3β
NF-κB
Phosphorylation
Proliferation
Therapeutic target
Wnt signaling
β-catenin

ASJC Scopus subject areas

Molecular Biology
Biophysics
Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2005.07.041

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title = "Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation",

abstract = "Glycogen synthase kinase 3β (GSK3β) reportedly has opposing roles, repressing Wnt/β-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-κB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3β in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3β expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of β-catenin oncoprotein in the tumor cells. Inhibition of GSK3β activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3β activity by chemical inhibitors and its expression by RNA interference targeting GSK3β induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3β in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.",

keywords = "Apoptosis, Cell survival, Colorectal cancer, Glycogen synthase kinase 3β, NF-κB, Phosphorylation, Proliferation, Therapeutic target, Wnt signaling, β-catenin",

author = "Abbas Shakoori and Andrei Ougolkov and Zhi, {Wei Yu} and Bin Zhang and Modarressi, {Mohammad H.} and Billadeau, {Daniel D.} and Masayoshi Mai and Yutaka Takahashi and Toshinari Minamoto",

note = "Funding Information: We thank Dr. Hiroyasu Esumi (National Cancer Center Research Institute, Japan) for reviewing the manuscript, and Mr. Michael Meyer for editorial assistance. This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture (to T.M.), from the Ministry of Health, Labour and Welfare (to T.M.), and from the Japan Society for the Promotion of Science (to T.M., A.O., and B.Z.). ",

year = "2005",

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doi = "10.1016/j.bbrc.2005.07.041",

language = "English (US)",

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T1 - Deregulated GSK3β activity in colorectal cancer

T2 - Its association with tumor cell survival and proliferation

AU - Shakoori, Abbas

AU - Ougolkov, Andrei

AU - Zhi, Wei Yu

AU - Zhang, Bin

AU - Modarressi, Mohammad H.

AU - Billadeau, Daniel D.

AU - Mai, Masayoshi

AU - Takahashi, Yutaka

AU - Minamoto, Toshinari

N1 - Funding Information: We thank Dr. Hiroyasu Esumi (National Cancer Center Research Institute, Japan) for reviewing the manuscript, and Mr. Michael Meyer for editorial assistance. This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture (to T.M.), from the Ministry of Health, Labour and Welfare (to T.M.), and from the Japan Society for the Promotion of Science (to T.M., A.O., and B.Z.).

PY - 2005/9/9

Y1 - 2005/9/9

N2 - Glycogen synthase kinase 3β (GSK3β) reportedly has opposing roles, repressing Wnt/β-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-κB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3β in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3β expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of β-catenin oncoprotein in the tumor cells. Inhibition of GSK3β activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3β activity by chemical inhibitors and its expression by RNA interference targeting GSK3β induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3β in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

AB - Glycogen synthase kinase 3β (GSK3β) reportedly has opposing roles, repressing Wnt/β-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-κB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3β in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3β expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of β-catenin oncoprotein in the tumor cells. Inhibition of GSK3β activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3β activity by chemical inhibitors and its expression by RNA interference targeting GSK3β induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3β in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

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KW - Cell survival

KW - Colorectal cancer

KW - Glycogen synthase kinase 3β

KW - NF-κB

KW - Phosphorylation

KW - Proliferation

KW - Therapeutic target

KW - Wnt signaling

KW - β-catenin

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ER -

Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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