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Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Oncogene volume 26, pages 6372–6385 (2007)Cite this article

Abstract

Indirubin-3′-monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3′-monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3′-monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptor-mediated cell signaling. Indirubin-3′-monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3′-monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3′-monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3′-monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3′-monoxime that may have clinical implications.

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Abbreviations

AML:

acute myeloid leukemia

CDK:

cyclin-dependent kinase

FCS:

fetal calf serum

FGFR:

FGF receptor

HSPG:

heparan sulfate proteoglycan

JNK:

c-Jun N -terminal kinase

Rb:

retinoblastoma protein

TCA:

trichloroacetic acid

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Acknowledgements

YZ is a PhD student at the University of Oslo, Faculty of Medicine, supported by the Norwegian Cancer Society. The skilful assistance with the cell cultures of Anne Engen and Anne Berit Dyve is gratefully acknowledged. This work was supported by grant DNK, T-974651001 from the Norwegian Cancer Society. We are grateful to Professors Jahn Nesland and Sjur Olsnes for their support.

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Authors and Affiliations

  1. Department of Biochemistry, Institute for Cancer Research at The National Hospital – The Norwegian Radium Hospital, University of Oslo, Oslo, Norway

    Y Zhen, V Sørensen, Y Jin & A Więdłocha

  2. Department of Pathology, Institute for Cancer Research at The National Hospital – The Norwegian Radium Hospital, University of Oslo, Oslo, Norway

    Y Zhen & Z Suo

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Correspondence to A Więdłocha.

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Zhen, Y., Sørensen, V., Jin, Y. et al. Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK. Oncogene 26, 6372–6385 (2007). https://doi.org/10.1038/sj.onc.1210473

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