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Research Articles: Therapeutics, Targets, and Development

Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Departments of ¹ Genetics, Cell Biology, and Anatomy, ² Pathology and Microbiology, and ³ Internal Medicine-Section of Oncology/Hematology, Center for Research in Leukemia and Lymphoma, University of Nebraska Medical Center, Omaha, Nebraska and ⁴ Nebraska Wesleyan University, Lincoln, Nebraska

Requests for reprints: Shantaram S. Joshi, Department of Genetics, Cell Biology, and Anatomy, Center for Research in Leukemia and Lymphoma, University of Nebraska Medical Center, Omaha, NE 68198-6395. Phone: 402-559-4165; Fax: 402-559-3400. E-mail: ssjoshi{at}unmc.edu

Abstract

Mantle cell lymphoma (MCL) has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival of only 3 to 4 years. Therefore, a better understanding of the underlying mechanisms that regulate MCL proliferation/survival is needed to develop an effective therapy. Because sonic hedgehog (Shh)-GLI signaling has been shown to be important in the proliferation and survival of several cancers, and no such information is available for MCL, this study was undertaken. Our results show that the molecules associated with Shh-GLI signaling, such as PTCH and SMO receptors, and GLI1 and GLI2 target transcription factors were expressed in the human MCL cell lines and primary MCL cells from patients. Perturbation of this signaling in the presence of exogenous Shh/cyclopamine significantly (P < 0.001) influenced the proliferation of JVM2 MCL cells. Furthermore, down-regulation of GLI transcription factors using antisense oligonucleotides not only resulted in significantly (P < 0.001) decreased proliferation of the MCL cells but also significantly (P < 0.05) increased their susceptibility to chemotherapeutic drug, doxorubicin. Also, down-regulation of GLI decreased cyclin D1 and BCL2 transcript levels, which suggests that these key molecules might be regulated by GLI in MCL. Thus, our results indicate a significant role for Shh-GLI signaling in the proliferation of MCL, and molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL. [Mol Cancer Ther 2008;7(6):1450–60]

Grant support: The Lymphoma Research Foundation; summer fellowship by NIH grant P20 RR016469 from the INBRE Program of the National Center for Research Resources (K. Emanuel).

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.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/19/07; revised 3/31/08; accepted 4/15/08.