Apoptosis Inhibitors As A New Class of Tumor Progression Factors

5 October, 1999

Apoptosis inhibitors as a new class of tumor progression factors

Upon stimulation of apoptosis, CD95 (APO-1/Fas) initially recruits a Fas-associated death domain protein (FADD) and caspase-8 (FLICE, namely FADD-like interleukin-1beta-converting enzyme) into the death-inducing signaling complex (DISC). This initial apoptotic process may be modulated by several regulatory proteins such as caspase inhibitors, apoptosis-inhibitor Bcl-2 homologues and death-effector-domain-containing proteins. The last proteins were recently identified to also possess apoptosis-inhibiting functions with sequence homology to caspase-8 and termed FLICE-inhibitory proteins (FLIP; Irmler M et al, 1997: uid=9217161). There are cellular and viral members of the FLIP family. FLIP is highly expressed in tumor cells, T lymphocytes and healthy myocytes. Cellular FLIP has two isoforms, short form FLIPs structurally related to viral FLIP and long form FLIP(L). FLIP blocks caspase-8 activation at the DISC and thereby inhibits CD95-mediated apoptosis. During this process, both caspase-8 and FLIP undergo cleavage, generating two stable intermediates of 43 kDa that stay bound to the DISC (Scaffidi C et al, 1999: uid=9880531).
The Kaposi's sarcomaﾐassociated herpesvirus (KSHV)-FLIP is expressed by human herpesvirus 8 (HHV-8), which is associated with malignancies such as Kaposi's sarcoma and certain lymphomas. Djerbi M et al (J Exp Med 190, 1025:1999) have shown recently that KSHV-FLIP protects cells from Fas-mediated apoptosis by inhibiting caspase activation and permits clonal growth in the presence of death stimuli in vitro. Further in vivo, murine B lymphoma cells (A20) transduced with KSHV-FLIP rapidly developed into aggressive tumors showing a high rate of survival and growth. This appeared to be due to the tumor-progressive nature of KSHV-FLIP that results from the prevention of death receptorﾐinduced apoptosis triggered by conventional T cells. In Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL), some cell lines are known to have a marked resistance to Fas-mediated apoptosis, although FADD and caspase-8 are expressed normally. Tepper CG and Seldin MF (1999: uid=10477698) found that the ratio of caspase-8 to FLIP transcript level is important, and as measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. The modification of the caspase-8/FLIP transcript ratio by caspase-8 or FLIP overexpression was able to alter the susceptibility status of the cell lines tested. Medema JP et al (J Exp Med 190, 1033: 1999) have also reported that two murine tumors escaped from T cell-dependent immunity in vivo by expressing cellular FLIP. In fact, tumors were selected in the environment for the elevated level of FLIP expression. The cellular FLIP is found overexpressed in some human melanomas, and already in 1998 (Griffith TS et al, 1998: uid=9743343) it was shown that the FLIP expression was highest in the TRAIL (TNF-related apoptosis-inducing ligand)-resistant melanomas, while being low or undetectable in the TRAIL-sensitive melanomas.

Consequently, the tumor resistance to apoptosis is controlled by intracellular regulators of apoptosis, and antiapoptotic protein FLIP may represent a naturally occurring tumorigenic effect and be regarded as a new class of tumor progression factors. It may be a reasonable thinking that anti-FLIP compounds help maintain T cell-dependent immuninity in vivo against tumorigenesis, and that such compounds could be found, because of structural relatedness, in the screening of caspase inhibitors that have been extensively carried out for different therapeutic purposes. It is not known whether or not anti-FLIP activity exists in natural food ingredients, the hunt for which would also be of considerable interest.

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