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GSK3 inhibitors enhance retinoic acid receptor activity and induce the differentiation of retinoic acid-sensitive myeloid leukemia cells

Leukemia volume 25, pages 1914–1918 (2011)Cite this article

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Glycogen synthase kinase3 (GSK3) is an ubiquitously expressed serine threonine kinase originally characterized (and named) as an enzyme, which phosphorylated and inactivated glycogen synthase, an important mediator of glycogen biosynthesis.1 However, GSK3 has subsequently been shown to phosphorylate a wide range of cellular proteins and to have a central role in multiple cellular functions governing cell metabolism, gene expression, cell division, apoptosis, stem cell maintenance and differentiation.2 GSK3 includes two closely related isoforms GSK3α and GSK3β, which exhibit 97% sequence identity within their catalytic domains, but which are encoded by two separate non-functionally equivalent genes. GSK3-mediated phosphorylation has been implicated in regulating the proteolytic degradation of potential oncogenic proteins including c-myc, c-jun, cyclin D1, cyclin E and Notch1(ref.3) suggesting that activated GSK3 acts as a tumor suppressor. In contrast, inhibiting GSK3 triggers the apoptosis of colorectal cancer cell lines,4 and pharmacological inhibitors of GSK3 inhibit the proliferation and/or trigger the differentiation of MLL-oncogene-associated biphenotypic leukemia.5 Thus GSK3 appears to act as a tumor suppressor in some cell types although enhancing anti-apoptotic and/or leukemogenic activity in others.

These same GSK3 chemical inhibitors also induce morphologic granulocytic differentiation of the ATRA-responsive HL60 and ML1 myeloid cell lines, and this is also accompanied by enhanced expression of Cd11b (data not shown). To determine whether there is a synergistic effect between ATRA and GSK3 inhibitors in myeloid leukemia cell differentiation, we treated NB4 cells using a combination of both drugs at concentrations that exhibit only a minimal effect on differentiation as single agents. We observed that the drug combination significantly induced morphologic granulocytic differentiation of NB4 cells with concurrent enhanced Cd11b expression (Figure 2e).

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Acknowledgements

This study was supported by NIH RO1 CA118971 (to SJC) and the Samuel Waxman Cancer Research Foundation (SWCRF).

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  1. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    J Si, L Mueller & S J Collins

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  1. J Si
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Correspondence to S J Collins.

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Si, J., Mueller, L. & Collins, S. GSK3 inhibitors enhance retinoic acid receptor activity and induce the differentiation of retinoic acid-sensitive myeloid leukemia cells. Leukemia 25, 1914–1918 (2011). https://doi.org/10.1038/leu.2011.171

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