Gap junctions: the "kiss of death" and the "kiss of life"

Cells expressing herpes simplex-thymidine kinase (HSV-tk) can be killed "in vitro" within 5 days of treatment with 20 mu M ganciclovir (GCV) and trans mit this toxicity to adjacent cells lacking HSV-tk; this phenomenon was ter med "bystander effect" or "kiss of death", On testing a large number of cel l lines in vitro, a wide range of sensitivity to GCV-mediated bystander kil ling has been reported. Although intercellular transfer of GCV metabolites through gap junction channels seems to be a likely mechanism for the "kiss of death'', some studies suggest that other pathways may contribute to indu ced apoptosis of neighboring cells. To further investigate the mechanism un derlying cell death mediated by HSV-tk and to evaluate the efficacy of gap junction channels formed by different connexins in this process, we have st ably transfected a virtually uncoupled mouse neuroblastoma cell line (N2A c ells) with different connexin-types expressed by neural cells (Cx32, Cx37, Cx40, Cx43) and co-cultured these cells with N2A cells stably transfected w ith Cx37 and HSV-tk, Here, we confirm our previous studies and those of oth ers that the extent of cell death and sensitivity to GCV depend on the degr ee of connexin expression in transfectants, Further, we show that the bysta nder effect also depends on which connexin is expressed; reported dispariti es regarding the extent of GCV-mediated cellular apoptosis are likely due b oth to the degree of functional coupling and the type of connexin expressed . These results support the notion that gap junction hemichannels formed of certain connexins are more likely than others to pair functionally with Cx 37, and suggest co-transfection strategies that might prove effective in se nsitizing tumor cell populations to GCV, In addition, potential application s are discussed for use of the ''good Samaritan effect'', a mechanism by wh ich bystander cells have been suggested to prevent cytotoxicity. (C) 2000 E lsevier Science B.V. All rights reserved.