Anti-tumor activity of gene transfer of the membrane-stable CD40L mutant into lung cancer cells.
Gene transfer of CD40 ligand (CD40L) holds promise as a novel therapy for lymphoid malignancies and a number of solid carcinomas because of its multiple anti-tumor activities. However, membrane-bound CD40L can be cleaved into a soluble form, sCD40L, which contributes to systemic inflammatory and cardiovascular diseases, and induces survival signals in the absence of protein synthesis block, suggesting a deleterious side effect of CD40L gene therapy. We generated a plasmid encoding non-cleavable human CD40L mutant (pcDNA3.1+-CD40L-M) to determine the direct anti-proliferative and pro-apoptotic effects in CD40-positive lung adenocarcinoma cell line A549, to verify activation of immature dentritic cells (DCs) by co-cultivation with the transfected A549 cells and to evaluate the lower expression of sCD40L relative to that of wild-type CD40L (CD40L-WT) transfectant in cell-free supernatants. These studies suggest that gene transfer of the membrane-stable CD40L mutant into CD40-positive cells may provide an efficient and safe method to treat non-small cell lung cancer.
Xu
Wei
W
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 Jiangsu, PR China.
Li
Yan
Y
Wang
Xueli
X
Wang
Cuiyu
C
Zhao
Weihong
W
Wu
Jianqing
J
D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017209:Apoptosis; D001483:Base Sequence; D023201:CD40 Ligand / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology*; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D055550:Protein Stability; D013997:Time Factors; D014162:Transfection
D023201:CD40 Ligand