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Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation

Oncogene volume 21, pages 8852–8861 (2002)Cite this article

Abstract

Cyclin D1 is a proto-oncogene that is overexpressed in many cancers including breast and prostate. It plays a role in cell proliferation through activation of cyclin-dependent kinases. Curcumin, a diferuloylmethane, is a chemopreventive agent known to inhibit the proliferation of several breast and prostate cancer cell lines. It is possible that the effect of curcumin is mediated through the regulation of cyclin D1. In the present report we show that inhibition of the proliferation of various prostate, breast and squamous cell carcinoma cell lines by curcumin correlated with the down-regulation of the expression of cyclin D1 protein. In comparison, the down-regulation by curcumin of cyclin D2 and cyclin D3 was found only in selective cell lines. The suppression of cyclin D1 by curcumin led to inhibition of CDK4-mediated phosphorylation of retinoblastoma protein. We found that curcumin-induced down-regulation of cyclin D1 was inhibited by lactacystin, an inhibitor of 26S proteosome, suggesting that curcumin represses cyclin D1 expression by promoting proteolysis. We found that curcumin also down-regulated mRNA expression, thus suggesting transcriptional regulation. Curcumin also inhibited the activity of the cyclin D1 promoter-dependent reporter gene expression. Overall our results suggest that curcumin down-regulates cyclin D1 expression through activation of both transcriptional and post-transcriptional mechanisms, and this may contribute to the antiproliferative effects of curcumin against various cell types.

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Abbreviations

IκB:

inhibitory subunit of NF-κB

CDK:

cyclin-dependent kinase

SCC:

squamous cell carcinoma

IKK:

IκBα kinase

MTT:

tetrazolium salt- 3-(4-5 dimethylthiozol-2-yl) 2-5 diphenyl-tetrazolium bromide

luc:

luciferase

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Acknowledgements

This research was supported by The Clayton Foundation for Research (to BB Aggarwal), by Department of Defense of the US Army Breast Cancer Research Program BC010610 (to BB Aggarwal), by P50 Head and Neck SPORE grant from National Institute of Health (to BB Aggarwal), and by the Department of Defense of the US Army Prostate Cancer Research Program PC010496 (to M Liu). We would like to thank Walter Pagel for a careful review of the manuscript.

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Authors and Affiliations

  1. Department of Bioimmunotherapy, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Asok Mukhopadhyay, Sanjeev Banerjee & Bharat B Aggarwal

  2. Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, and Department of Medical Biochemistry and Genetics, Texas A&M University System Health Sciences Center, Houston, 77030, Texas, TX, USA

    Lewis Joe Stafford, Chunzhi Xia & Mingyao Liu

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  1. Asok Mukhopadhyay
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Correspondence to Bharat B Aggarwal.

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Mukhopadhyay, A., Banerjee, S., Stafford, L. et al. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene 21, 8852–8861 (2002). https://doi.org/10.1038/sj.onc.1206048

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