E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models.

Abstract

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.

• Authors: L Garcia-Rodríguez, D Abate-Daga, A Rojas, J R González, C Fillat
• Journal: Gene therapy (Gene Ther) Vol. 18 Issue 1 Pg. 73-81 (Jan 2011) ISSN: 1476-5462 [Electronic] England
• PMID: 20720574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cadherins
• Thymidine Kinase
• Ganciclovir

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Bystander Effect (genetics)
• Cadherins (genetics, metabolism)
• Ganciclovir (administration & dosage, pharmacology)
• Genes, Transgenic, Suicide (genetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Pancreatic Neoplasms (genetics, therapy)
• Retroviridae (genetics, metabolism)
• Simplexvirus (genetics, metabolism)
• Thymidine Kinase (administration & dosage, genetics, metabolism)
• Transfection
• Tumor Cells, Cultured