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

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

^* To whom correspondence should be addressed. 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]

Key Words: apoptosis, autophagy, rhomboid, RHBDF1, siRNA