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

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

250 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
Externally published	Yes

Bibliographical 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.).

Keywords

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

UN SDGs

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

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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.",

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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.). ",

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T2 - Its association with tumor cell survival and proliferation

AU - Shakoori, Abbas

AU - Ougolkov, Andrei

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AU - Zhang, Bin

AU - Modarressi, Mohammad H.

AU - Billadeau, Daniel D.

AU - Mai, Masayoshi

AU - Takahashi, Yutaka

AU - Minamoto, Toshinari

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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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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