Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL)

Expression of the adenovirus serotype 5 (Ad5) EIA oncogene sensitizes cells to apoptosis by TNF-alpha and Fas-ligand, Because TNF-related apoptosis-in ducing ligand (TRAIL) kills cells in a similar manner as TNF-alpha and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by T RAIL. To test this hypothesis, we examined TRAIL-induced killing of human m elanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following eit her infection,vith Ad5 or stable transfection with Ad5-E1A, E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-indu ced killing, but Ad5-infected cells expressing equally high levels of E1A p rotein remained resistant to TRAIL, Infection of A2058-E1A cells with Ad5 r educed their sensitivity to TRAIL dependent killing, Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity t o TRAIL-induced killing conferred by transfection with E1A, E1B and E3 gene products have been shown to inhibit TNF-alpha- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined b y using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptib le to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A205 8-E1A cells was not inhibited by infection with H5dl327. Infection with H5d l250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection, In summary, expression of Ad5-E1A gene products se nsitizes cells to TRAIL-dependent killing whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.