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Research Articles: Therapeutics, Targets, and Development

Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells

¹ Department of Investigational Cancer Therapeutics (Phase I Program), ² Department of Leukemia, Division of Cancer Medicine, and ³ Department of Bioinformatics and Computational Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Razelle Kurzrock, Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0455, Houston, TX 77030. Phone: 713-794-1226; Fax: 713-745-2374. E-mail: rkurzroc{at}mdanderson.org

Abstract

Background: A major challenge in cancer chemotherapy has been developing safe and clinically efficacious chemotherapeutic agents. With its low toxicity profile, curcumin (diferuloylmethane), a naturally occurring flavinoid derived from the rhizome of Curcuma longa, has great promise. In vitro and in vivo preclinical studies have shown its inhibitory anticancer, antioxidant, anti-inflammatory, antiproliferative, and proapoptotic activities. The multiple mechanisms of the antitumor effect of curcumin putatively include down-regulating the expression of gene products such as nuclear factor-B, growth suppression, inducing apoptosis, and modulating various signal transduction pathways and the expression of many oncogenes. The mechanisms underlying the antitumor activity of curcumin have not, however, been completely delineated. Methods: An oligonucleotide microarray chip was developed and used to profile microRNA (miRNA) expressions in pancreatic cells treated with curcumin. Transcripts with regulated expression patterns on the arrays were validated by real-time PCRs. Additionally, potential mRNA targets were analyzed bioinformatically and confirmed with flow cytometry experiments. Results: Curcumin alters miRNA expression in human pancreatic cells, up-regulating miRNA-22 and down-regulating miRNA-199a*, as confirmed by TaqMan real-time PCR. Upregulation of miRNA-22 expression by curcumin or by transfection with miRNA-22 mimetics in the PxBC-3 pancreatic cancer cell line suppressed expression of its target genes SP1 transcription factor (SP1) and estrogen receptor 1 (ESR1), while inhibiting miRNA-22 with antisense enhanced SP1 and ESR1 expression. Conclusions: These observations suggest that modulation of miRNA expression may be an important mechanism underlying the biological effects of curcumin. [Mol Cancer Ther 2008;7(3):464–73]

Grant support: P20 CA101936; The Topfer Family Fund for Pancreatic Cancer Research; M. D. Anderson Cancer Center CORE grant NIH CA-16672; and also supported by Grant Number RR024148 from the National Center for Research Resources, a component of the NIH Roadmap for Medical Research (http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp), grant RR024148.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ N. Dhillon, B.B. Aggarwal, R.A. Newman, et al. Phase II trial of curcumin, an NF-B inhibitor, in patients with advanced pancreatic cancer, submitted for publication.

⁵ http://www.sanger.ac.uk/Software/Rfam/mirna/index.shtml

⁶ http://www.sanger.ac.uk/Software/Rfam/microRNAna/

⁷ http://pictar.bio.nyu.edu

⁸ http://genes.mit.edu/targetscan

⁹ http://www.sanger.ac.uk/Software/Rfam

¹⁰ http://www.ncbi.nlm.nih.gov

¹¹ http://www.perl.com

¹² http://bio.perl.org

¹³ http://pictar.bio.nyu.edu

¹⁴ http://genes.mit.edu/targetscan

Received 11/ 8/07; revised 1/15/08; accepted 1/22/08.

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