This Article Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kandasamy, K. Articles by Kraft, A. S. Search for Related Content PubMed PubMed Citation Articles by Kandasamy, K. Articles by Kraft, A. S.

Research Articles: Therapeutics, Targets, and Development

Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3'-untranslated region

Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina

Requests for reprints: Andrew S. Kraft, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Suite 124, Charleston, SC 29425. Phone: 843-792-8284; Fax: 843-792-9456. E-mail: Kraft{at}musc.edu

Abstract

Addition of proteasome inhibitor PS-341 (VELCADE, bortezomib) to prostate cancer cells enhances cell death mediated by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). PS-341 sensitizes prostate cancer cells to TRAIL-induced apoptosis by increasing TRAIL receptors (DR5), inhibiting protein degradation, and elevating DR5 mRNA. Investigations into how PS-341 regulates the stability of DR5 mRNA revealed that PS-341 increased DR5 mRNA by extending its half-life from 4 to 10 h. The 2.5-kb 3'-untranslated region of the DR5 gene stabilized a heterologous gene in LNCaP human prostate cancer cells, suggesting the importance of this mRNA sequence. In contrast, human prostate cancer cell lines PC-3 and DU145 do not show this stabilization, suggesting cell specificity. PS-341 treatment of LNCaP cells increases the level of specific cytoplasmic mRNA-binding proteins, including AUF-1 isoforms, hnRNP C1/C2, and HuR proteins. In UV cross-linking experiments, after PS-341 treatment, the HuR protein markedly increases binding to specific sequences in the DR5 3'-untranslated region. In LNCaP cells treated with PS-341, small interfering RNA–mediated knockdown of HuR markedly decreases the half-life of DR5 mRNA, indicating that HuR is essential for mRNA stabilization. HuR protein is ubiquitinated, suggesting that PS-341 increases this protein by preventing its degradation. These experiments implicate modulation of mRNA stability as a novel mechanism by which proteasome inhibitors function, sensitizing cancer cells to antineoplastic agents. [Mol Cancer Ther 2008;7(5):1091–100]

Grant support: NIH grant R01 CA104710 (A.S. Kraft).

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.

¹ Supplementary materials for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² D. Dixon et al. University of South Carolina, unpublished data.

Received 12/ 5/07; revised 2/20/08; accepted 2/25/08.