TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeuticintervention

To determine whether the apoptotic machinery of thyroid cancer cells is fun ctional and could be activated for tumoricidal purposes, we examined the ap optosis induced by the cytokines TNF-alpha, Fas and TRAIL in thyroid cancer cell lines, NPA. and SW579. Interestingly, out of these cytokines, only TR AIL was able to trigger significant apoptosis, The tumoricidal effect of TR AIL was further enhanced by CHX, suggesting the presence of CHX-sensitive i nhibitor(s) of apoptosis in these thyroid cancer cell lines, The anti-apopt otic proteins like FLAME-1, Bcl-2 and Bcl-xL are believed to be such CHX-se nsitive inhibitors in various types of cancer cells. We, however provide th e evidence using NPA and SW579 cell lines that these proteins were not affe cted by the CHX treatment in thyroid cancer cells. The apoptosis of thyroid cancer cells,vas mediated by the classical activation of caspases that in turn activated the DNA Fragmentation Factor (DFF-45). To elucidate the role of individual caspases in TRAIL-mediated apoptosis, the inhibitory effects of several general and specific tetrapeptide caspase inhibitors were studi ed. The inhibitors of caspase-1, -6, -8, and -9 as well as general upstream inhibitors of apoptosis could dramatically inhibit TRAIL-induced apoptosis in thyroid cancer cells. Caspase-2 and -3 inhibitors, on the other hand, h ad no significant effect. When the cells were treated with either agonistic Fas antibody (CH11) or TNF-alpha, no apoptotic changes mere observed, The apoptosis induced by agonistic Fas Ab could be seen only after a prolonged exposure (24 h) to CHX, whereas TNF-alpha had no effect even in the presenc e of CHX. The efficacy of TRAIL nas also tested on other types of thyroid c ancer cells like ARO, FRO (anaplastic carcinoma) and TPC-1 (papillary carci noma) and compared to that triggered by other death inducing cytokines Fast and TNF-alpha. Again TRAIL tvas more potent in triggering apoptosis than F as and TNF-alpha. Since TRAIL is effective in selectively killing thyroid t umor cells without affecting normal thyrocytes and also does not cause orga n toxicity and inflammation in vivo, its potential for the treatment of thy roid cancer seems very promising.