Differentiation-inducing factor-1 suppresses the expression of c-myc in the human cancer cell lines

Differentiation-inducing factor-1 (dif-1),a morphogen for dictyostelium discoideum,inhibits the proliferation of human cancer cell lines by suppressing the wnt/β-catenin signaling pathway. in this study,we examined the effect of dif-1 on c-myc,a target gene product of the wnt/β-catenin signaling pathway,mainly using hct-116 colon cancer cells. dif-1 strongly reduced the amount of c-myc protein in time-and concentration-dependent manners and reduced c-myc mrna expression by inhibiting promoter activity through the tcf binding sites. the effect of dif-1 on c-myc was also confirmed using the human cervical cell line hela. pretreatment with the proteasome inhibitor mg132 or glycogen synthase kinase-3β (gsk-3β) inhibitors (licl and sb216763) attenuated the effect of dif-1,suggesting that dif-1 induced c-myc protein degradation through gsk-3β activation. furthermore,we examined whether c-myc was involved in the anti-proliferative effect of dif-1 using c-myc-overexpressing cells and found that c-myc was associated with the anti-proliferative effect of this compound. these results suggest that dif-1 inhibits c-myc expression by inhibiting promoter activity and inducing protein degradation via gsk-3β activation,resulting in the inhibition of cell proliferation. since c-myc seems to be profoundly involved in accelerated proliferation of various malignant tumors,dif-1 may have a potential to develop into a novel anti-cancer agent. © the japanese pharmacological society.