Tylophorine compounds exert anti-cancer activity by targeting a ribonucleoprotein complex containing caprin-1 and c-Myc mRNA

Tylophorine and its derivatives exhibit anti-cancer activities, but their cellular targets remain to be elucidated. We used a biotinylated tylophorine derivative to probe for the interacting cellular target(s) of tylophorine. Tylophorine targets and sequesters caprin-1, G3BP1, c-Myc mRNA and cyclin D1/D2 mRNA-associated ribonucleoprotein complexes to the polysomal fractions, thereby repressing the protein expression of the associated mRNA-transcripts. Gene expression profiling and gain-of-c-Myc-function experiments in tylophorine-treated carcinoma cells revealed that the down-regulation of c-Myc contributes to the anti-oncogenic effects of tylophorine. Furthermore, the potent tylophorine derivative dibenzoquinoline-33b elicited a similar effect, as c-Myc protein levels were also decreased in xenograft tumors treated with dibenzoquinoline-33b.Thus, tylophorine compounds exert anti-cancer activity predominantly by targeting and sequestering the caprin-1 protein and c-Myc mRNA associated ribonucleoprotein co...