FAP-1 has been considered as one of the protein inhibitors in Fas-mediated apoptosis. However, we obtained Fas-susceptible clones by transduction of FAP-1 cDNA to FAP-1-negarive SW480 colon cancer cell line, which expressed Fas on the surface but was strongly resistant to Fas-mediated apoptosis. In the clones, caspase 8 and caspase 3 were fully activated by agonistic anti-Fas antibody treatment. Bcl-2 family proteins did not seem to relate to the high susceptibility of these clones, because caspase 9 was not activated. Transfection of FAP-1 did not suppress the survival actions of IGF-1 which enhance survival signal through Akt phsphorylation. Therefore, it was suggested that unknown factors might contribute this phenomenon. Then, we analyzed cDNA microarrays to compare mRNA levels of various genes between one of the Fas-sensitive clone and LacZ-transfected or parental SW480. Expression of p21 upregulation was confirmed in the clones, but antisense treatment of p21 showed that it acted as an inhibitor against Fas-mediated apoptosis. Upregulation in 21 genes and downregulation in 29 genes were revealed by cDNA microarrays. These genes contained transcription factors and signal transduction molecules. FAP-1 might induce unbalance in the network of survival and inhibitory factors that suppressed Fas-mediated apoptosis and, as a result, enhance susceptibility against Fas-mediated apoptosis in SW480.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]