Tumour
necrosis factor (
TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells, but not in normal cells, and hence TRAIL has recently emerged as a novel anti-
cancer agent. Adult T-cell leukaemia
lymphoma (
ATLL) is a
neoplasm of T-lymphocyte origin aetiologically associated with human T-lymphotropic virus type 1 (HTLV-I), and is resistant to standard anti-
cancer therapy. We thus characterized the sensitivity of
ATLL cells to TRAIL in this study. Although most primary
ATLL cells and cell lines expressed TRAIL
death receptors on their surface, they showed only restricted sensitivity to TRAIL. Among the 10
ATLL cell lines examined, one was sensitive, but two had insufficient
death-receptor expression, two had an unknown resistant mechanism with abrogation of the death signal upstream of
caspase-8, and the remaining five showed attenuation of the signal in both extrinsic and intrinsic pathways by X-linked inhibitor of apoptosis and Bcl-2/Bcl-xL respectively. Furthermore, the level of HTLV-I tax expression was significantly correlated to TRAIL resistance. Interestingly,
ATLL cells themselves expressed TRAIL on the cell surface. Constitutive production of TRAIL may offer resistance, thus allowing the development of TRAIL-resistant
ATLL cells. Consequently, the resistant mechanism in
ATLL cells against TRAIL was assigned to multiple factors and was not explained by a definitive single agent.