In vitro adenoviral vector p53-mediated transduction and killing correlates with expression of coxsackie-adenovirus receptor and alpha(nu)beta5 integrin in SUDHL-1 cells derived from anaplastic large-cell lymphoma.
Adenoviral vector-mediated p53 expression induced apoptosis is a well established gene therapy approach that has been evaluated extensively in epithelial tumors but only recently in lymphoid malignancies mainly due to the known resistance of the lymphoid lineage to adenovirus infection. Recently, it was shown that this resistance is not absolute and that cell lines derived from anaplastic large cell lymphoma (ALCL) and some other lymphoid malignancies are efficiently transduced by adenoviral vectors. Normal circulating T lymphocytes do not express coxsackie-adenovirus receptor (CAR) and alpha(nu)beta integrins and are relatively resistant to infection by adenovirus. These molecules serve as receptors for adenovirus entry into the cells. ALCL-derived SUDHL-1 cells were evaluated for transduction efficiency and expression of p53 after infection with an adenoviral vector containing wild-type p53 (AdWTp53). Cells derived from ALCL and circulating mononucleated cells (MNCs) were also evaluated for expression of CAR and alpha(nu)beta integrins. AdWTp53-mediated expression of p53 resulted in p21/WAF1 induction, G1 arrest, and apoptosis in SUDHL-1 cells. The expression of CAR and alpha(nu)beta5 integrin was high in SUDHL-1 cells and comparable to levels observed with epithelial tumor cells, but it was absent in MNCs. The susceptibility to adenoviral vector transduction of the tumor-derived cells implies an important biological difference between them and circulating MNCs, possibly underlying the malignant transformation that ALCL cells undergo. Further studies will be required to evaluate this initial observation in more cell lines and tissue derived from ALCL.
Turturro
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Human Gene Therapy Research Institute, Iowa Methodist Medical Center, and VA Central Iowa Health Care System, Des Moines 50309-3203, USA. turturfm@ihs.org
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D000256:Adenoviridae / Q000502:physiology; D002453:Cell Cycle; D002470:Cell Survival; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D016158:Genes, p53; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000473:pathology*; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D019030:Receptors, Vitronectin; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016023:Integrins; D011991:Receptors, Virus; D019030:Receptors, Vitronectin; D016159:Tumor Suppressor Protein p53; C064660:integrin alphaVbeta5