Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells.
FUS1 is a novel tumor suppressor gene identified in human chromosome 3p21.3 region. Loss of expression and deficiency of posttranslational modification of FUS1 protein have been found in a majority of human lung cancers. Restoration of wild-type FUS1 in 3p21.3-deficient human lung cancer cells exhibited a potent tumor suppression function in vitro and in vivo. In this study, we evaluated the combined effects of FUS1 and tumor suppressor p53 on antitumor activity and explored the molecular mechanisms of their mutual actions in human non-small cell lung cancer (NSCLC) cells. We found that coexpression of FUS1 and p53 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle-mediated gene transfer significantly and synergistically inhibited NSCLC cell growth and induced apoptosis in vitro. We also found that a systemic treatment with a combination of FUS1 and p53 nanoparticles synergistically suppressed the development and growth of tumors in a human H322 lung cancer orthotopic mouse model. Furthermore, we showed that the observed synergistic tumor suppression by FUS1 and p53 concurred with the FUS1-mediated down-regulation of murine double minute-2 (MDM2) expression, the accumulation and stabilization of p53 protein, as well as the activation of the apoptotic protease-activating factor 1 (Apaf-1)-dependent apoptotic pathway in human NSCLC cells. Our results therefore provide new insights into the molecular mechanism of FUS1-mediated tumor suppression activity and imply that a molecular therapy combining two or more functionally synergistic tumor suppressors may constitute a novel and effective strategy for cancer treatment.
Deng
Wu-Guo
WG
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kawashima
Hiroyaki
H
Wu
Guanglin
G
Jayachandran
Gitanjali
G
Xu
Kai
K
Minna
John D
JD
Roth
Jack A
JA
Ji
Lin
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053477:Apoptotic Protease-Activating Factor 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; C495901:TP53 protein, human; C499993:TUSC2 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2