WWOX gene restoration prevents lung cancer growth in vitro and in vivo

Abstract

The WWOX (WW domain containing oxidoreductase) gene at the common fragile site, FRA16D, is altered in many types of cancer, including lung cancer. We have examined the tumor suppressor function of WWOX in preclinical lung cancer models. The WWOX gene was expressed in lung cancer cell lines through recombinant adenovirus (Ad) infection (Ad- WWOX ), and through a drug [ponasterone A, (ponA)]-inducible system. After WWOX restoration in vitro , endogenous Wwox protein-negative cell lines (A549, H460, and H1299) underwent apoptosis through activation of the intrinsic apoptotic caspase cascade in A549 and H460 cells. Ectopic expression of Wwox caused dramatic suppression of tumorigenicity of A549, H460, and H1299 cells in nude mice after Ad- WWOX infection and after ponA induction of Wwox expression in H1299 lung cancer cells. Tumorigenicity and in vitro growth of U2020 (Wwox-positive) lung cancer cells was unaffected by Wwox overexpression. This study confirms that WWOX is a tumor suppressor gene and is highly effective in preventing growth of lung cancer xenografts, whether introduced through viral infection or by induction of a silent WWOX transgene.

A Comparison and Catalog of Intrinsic Tumor Growth Models

“…4D from Fabbri 2005 was cropped from the graph because it was two orders of magnitude higher than the next largest tumor, making the other 12 trials impossible to distinguish. Despite its exclusion here, it was used in the fitting analysis.…”

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

“…Several tumor types, such as human breast tumors, overexpress aberrant transcripts (Driouch et al, 2002;Ludes-Meyers et al, 2003). Moreover, WWOX has the capacity to function as a tumor suppressor gene both in vitro and in vivo (Bednarek et al, 2001;Kuroki et al, 2004;Fabbri et al, 2005;Iliopoulos et al, 2007;LudesMeyers et al, 2007;Qin et al, 2007;Aqeilan et al, 2007bAqeilan et al, , 2007c. Together, these findings suggest that WWOX is a tumor suppressor gene.…”

In vivo restoration of RhoB expression leads to ovarian tumor regression

“…These observations prompted us to investigate the potential use of gene modification of tumor cells by RhoB, as has been suggested with other tumor suppressor genes, such as p53, Rb or WWOX. 18,19 Ovarian cancer is the most lethal of the gynecological malignancies with 75-80% of patients presenting with advanced-stage disease wherein the survival rate is only 15-20%. Patients undergoing an optimal tumor reductive surgery at presentation increase the disease-free interval, but most finally die of the disease.…”