Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Abstract

Expression of the adenovirus serotype 5 (Ad5) E1A oncogene sensitizes cells to apoptosis by TNF-α and Fas-ligand. Because TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar manner as TNF-α and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by TRAIL. To test this hypothesis, we examined TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following either infection with Ad5 or stable transfection with Ad5-E1A. E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-induced killing, but Ad5-infected cells expressing equally high levels of E1A protein remained resistant to TRAIL. Infection of A2058-E1A cells with Ad5 reduced their sensitivity to TRAIL-dependent killing. Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity to TRAIL-induced killing conferred by transfection with E1A. E1B and E3 gene products have been shown to inhibit TNF-α- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined by using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptible to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A2058-E1A cells was not inhibited by infection with H5dl327. Infection with H5dl250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection. In summary, expression of Ad5-E1A gene products sensitizes cells to TRAIL-dependent killing, whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

“…The Hs766T cells were highly insensitive to virusinduced cell killing with EC 50 values of 24 400 ± 8000, 17 400±5800 and 15 000±3000 ppc for Ad5, dl922-947 and dl1520, respectively. There were no significant differences between viruses in the murine Panc02 cells (EC 50 values of 2000 ppc) (Figure 1a). The non-replicating E1A-deleted mutant dl312 did not induce cell death at concentrations up to 1 Â 10 5 ppc in any cell line.…”

A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma

“…In contrast to the previous report by Yamanaka et al, 34 who showed that six HCC cell lines were resistant to TRAIL, we found that the Hep3B cells were sensitive to TRAIL by the Caspase-3 assay ( Figure 6). The different results may be due to the conformational structure of recombinant TRAIL, 35 E1A expression 36 or E1B-19k gene deletion. 37 Expression of AFP in human HCC cells varies greatly, ranging from essentially undetectable to extremely high levels.…”

Effective gene-viral therapy of leukemia by a new fiber chimeric oncolytic adenovirus expressing TRAIL: in vitro and in vivo evaluation

“…Because constitutive endocytosis and predominant intracellular location of some of the TRAIL receptors were reported previously (44,45), further studies are needed to determine whether TRAIL produced by SG235-TRAIL ligates the death receptors within intracellular organelles and thus triggers apoptosis. Additionally, adenovirus E1A gene expression in tumor cells was reported to enhance killing by TRAIL (46), which may contribute to enhanced apoptosis induced by SG235-TRAIL.…”