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Research Articles: Therapeutics, Targets, and Development

Human rhomboid family-1 gene silencing causes apoptosis or autophagy to epithelial cancer cells and inhibits xenograft tumor growth

Departments of ¹ Pathology and ² Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ³ Department of Pathology, University of Maryland School of Medicine, College Park, Maryland; and ⁴ Sirnaomics, Inc., Rockville, Maryland

Requests for reprints: Lu-Yuan Li, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, G12C, Pittsburgh, PA 15213. Phone: 412-623-1118; Fax: 412-623-4747. E-mail: lil{at}upmc.edu

Abstract

The rhomboid family of genes carry out a wide range of important functions in a variety of organisms. Little is known, however, about the function of the human rhomboid family-1 gene (RHBDF1). We show here that RHBDF1 function is essential to epithelial cancer cell growth. RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and the protein is readily detectable in human breast cancer or head and neck cancer cell lines. Silencing the RHBDF1 gene with short interfering RNA (siRNA) results in apoptosis in breast cancer MDA-MB-435 cells and autophagy in head and neck squamous cell cancer 1483 cells. The treatment also leads to significant down-modulation of activated AKT and extracellular signal-regulated kinase in the cells, suggesting that critically diminished strength of these growth signals may be the key attributes of the induction of cell death. Furthermore, silencing the RHBDF1 gene in MDA-MB-435 or 1483 xenograft tumors on athymic nude mice by using i.v. administered histidine-lysine polymer nanoparticle-encapsulated siRNA results in marked inhibition of tumor growth. Our findings indicate that RHBDF1 has a pivotal role in sustaining growth signals in epithelial cancer cells and thus may serve as a therapeutic target for treating epithelial cancers. [Mol Cancer Ther 2008;7(6):1355–64]

Grant support: Flight Attendant Medical Research Institute and Henry L. Hillman Foundation (L-Y. Li) and National Cancer Institute Head and Neck SPORE CA097190 (J.R. Grandis).

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.

Note: Current address for Z. Yan: Department of Neurology, Sun Yat-Sen University, Guangdong, People's Republic of China.

⁵ http://cgap.nci.nih.gov/

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/28/08; revised 3/27/08; accepted 3/30/08.