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

Research output: Contribution to journalArticle

203 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 languageEnglish (US)
Pages (from-to)1365-1373
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume334
Issue number4
DOIs
StatePublished - Sep 9 2005

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shakoori, A., Ougolkov, A., Zhi, W. Y., Zhang, B., Modarressi, M. H., Billadeau, D. D., Mai, M., Takahashi, Y., & Minamoto, T. (2005). Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferation. Biochemical and Biophysical Research Communications, 334(4), 1365-1373. https://doi.org/10.1016/j.bbrc.2005.07.041