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

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]

Human Rhomboid Family-1 Suppresses Oxygen-Independent Degradation of Hypoxia-Inducible Factor-1α in Breast Cancer

“…FLAG-RACK1 was constructed into pCI (Promega). RHBDF1 short hairpin RNA (shRNA) retroviral vector was derived from pSUPER.retro.puromycin (OligoEngine) and contains a 19-nucleotide sequence against RHBDF1 as described previously (11,12). 17-Allylamino-demethoxygeldamycin (17-AAG) and antibodies against b-actin, HA, and FLAG were purchased from Sigma.…”

“…In Drosophila, noncatalytic rhomboids were shown to prevent the cleavage of the substrates of rhomboid proteases by promoting their destabilization by endoplasmic reticulum-associated degradation (10). In human, RHBDF1 was shown to have a pivotal role in sustaining growth signals in epithelial cancers (11,12). RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and RHBDF1 gene silencing results in apoptosis or autophagy in breast cancer or head and neck cancer cells and inhibition of xenograft tumor growth (11).…”

“…In human, RHBDF1 was shown to have a pivotal role in sustaining growth signals in epithelial cancers (11,12). RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and RHBDF1 gene silencing results in apoptosis or autophagy in breast cancer or head and neck cancer cells and inhibition of xenograft tumor growth (11). RHBDF1 was found to participate in the modulation of Gprotein-coupled receptor-mediated transactivation of EGF receptor (12).…”

Regulation of Receptor Tyrosine Kinase Ligand Processing

“…iRhom1/RHB DF1 has been broadly implicated in growth control of cancer cells and EGFR signaling, although the mechanistic basis for this is unclear (Nakagawa et al 2005;Yan et al 2008). Recently, however, the cellular function of mammalian iRhoms has been revealed: iRhom2 is essential for the export of TACE from the ER, and thereby for the shedding of TACE substrates McIlwain et al 2012).…”

Lentivirus-mediated Silencing of Rhomboid Domain Containing 1 Suppresses Tumor Growth and Induces Apoptosis in Hepatoma HepG2 Cells

“…However, several investigations have provide strong evidence that rhomboid protease may play an important role in cancer cell growth and apoptosis. For example, human rhomboid family-1 (RHBDF1), a novel family member of rhomboid proteases, participates in the modulation of GPCR-mediated EGFR transactivation and disrupts growth signals in several cancer cell growth, including epithelial cancer, breast cancer, and head and neck squamous cancer cells (Yan et al, 2008;Zou et al, 2009). Rhomboid domain containing 1 (RHBDD1), an important gene highly expressed in the testis, is shown to participate in the cleavage of BIK and modulate BIK-medicated apoptosis (Wang et al, 2008).…”