Our results demonstrate that TRAIL-R2/DR5 up-regulation and apoptosis in 2D cultures of colon tumor cells undergoing ER stress is preceded by an early decrease in the expression levels of cFLIP proteins, which alters the caspase-8/FLIP ratio facilitating caspase-8 activation and apoptosis, as recently demonstrated in TRAIL-induced apoptosis [16, 17]. This evidence concerns the gene CASP8 and colonic neoplasm.