E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models.
The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.
Garcia-Rodríguez
L
L
Programa Gens i Malaltia, Centre de Regulació Genòmica, Parc de Recerca Biomèdica de Barcelona, UPF, Barcelona, Spain.
Abate-Daga
D
D
Rojas
A
A
González
J R
JR
Fillat
C
C
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D024201:Bystander Effect / Q000235:genetics; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D015774:Ganciclovir / Q000008:administration & dosage* / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015820:Cadherins; D013937:Thymidine Kinase; D015774:Ganciclovir