Open AccessWWOX gene restoration prevents lung cancer growth in vitro and in vivo
Author(s) -
Muller Fabbri,
Dimitrios Iliopoulos,
Francesco Trapasso,
Rami I. Aqeilan,
Amelia Cimmino,
Nicola Zanesi,
Sai Yendamuri,
Shuang Han,
Dino Amadori,
Kay Huebner,
Carlo M. Croce
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0505485102
Subject(s) - wwox , cancer research , lung cancer , biology , ectopic expression , suppressor , apoptosis , tumor suppressor gene , cancer , a549 cell , cancer cell , transgene , chromosomal fragile site , cell culture , gene , medicine , carcinogenesis , pathology , genetics , chromosome
TheWWOX (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 ofWWOX in preclinical lung cancer models. TheWWOX gene was expressed in lung cancer cell lines through recombinant adenovirus (Ad) infection (Ad-WWOX ), and through a drug [ponasterone A, (ponA)]-inducible system. AfterWWOX restorationin 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 andin vitro growth of U2020 (Wwox-positive) lung cancer cells was unaffected by Wwox overexpression. This study confirms thatWWOX 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 silentWWOX transgene.