Increased apoptosis and reduced replication efficiency of the E3 region-modified dl309 adenovirus in cancer cells.
The Adenovirus (Ad) dl309 mutant, which lacks several E3 region genes, has been used as the backbone for a number of replication selective cytopathic Ads designed to treat tumours. We report that dl309 has enhanced cytopathogenicity in a range of different cell lines when compared with Ad5. The E3 region modifications found in dl309 contributed to reduced late gene expression in both cocksackie-adenovirus receptor (CAR) positive and negative cells. We show that completion of the dl309 viral lifecycle was less efficient and apoptosis was triggered in the CAR negative K1 thyroid cancer-derived cell line. There was increased E1A expression in dl309-infected K1 cells, compared with Ad5, and significantly, whereas E1A in Ad5-infected cells was distributed both in the nuclear and cytoplasmic compartments, E1A was predominantly nuclear in dl309-infected K1 cells. From these results we conclude that the regions of dl309 that are deleted or otherwise modified can contribute to viral replication and inhibition of apoptosis, possibly indirectly by regulating E1A. These data have implications in the development of dl309-based Ads for the treatment of tumours in vivo.
Hibma
Merilyn H
MH
Virus Research Unit, Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand. merilyn.hibma@stonebow.otago.ac.nz
Real
Nicola C
NC
Wiles
Anna
A
Dobson-Le
Deirdre
D
Dix
Brett R
BR
Wynford-Thomas
David
D
Braithwaite
Antony W
AW
Royds
Janice A
JA
D000256:Adenoviridae / Q000472:pathogenicity* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis; D017503:Adenovirus E3 Proteins / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000472:pathogenicity* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D014774:Virulence; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017503:Adenovirus E3 Proteins; D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear