To elucidate the molecular mechanism(s) involved in the TRAIL-induced apoptosis sensitivity, we conducted the following experiments utilizing TRAIL-sensitive and -resistant glioma cells. We examined the expression of TRAIL receptors mRNA, but no significant differences were detected in those cells. TRAIL-resistant cells were sensitized to TRAIL-induced apoptosis by staurosporine pretreatment and preferentially expressed PKC epsilon. Since several lines of evidence suggest that PKC may play a protective role for apoptosis, we analyzed the involvement of PKC epsilon in TRAIL-induced apoptosis by an adeno virus vector expression system. We found that TRAIL susceptibility was augmented by the expression of a dominant negative PKC epsilon in TRAIL-resistant cells. Conversely, PKC epsilon introduction in TRAIL-sensitive cells resulted in the reduction of TRAIL-induced apoptosis. Taken together, these data suggest that PKCE may be a regulator of susceptibility to TRAIL-induced apoptosis in gliomas and probably other malignancies.