Targeting a ribonucleoprotein complex containing the caprin-1 protein and the c-Myc mRNA suppresses tumor growth in mice: an identification of a novel oncotarget
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Ya-Qi Qiu1,2, Cheng-Wei Yang1, Yue-Zhi Lee1, Ruey-Bing Yang3, Chih-Hao Lee4, Hsing-Yu Hsu1, Chien-Chung Chang2 and Shiow-Ju Lee1
1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan
2 Graduate Program of Biotechnology in Medicine, Institute of Molecular & Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
4 Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA
Shiow-Ju Lee, email:
Keywords: Caprin-1, c-Myc, Cyclin D, G3BP1, Processing Body
Received: October 02, 2014 Accepted: December 09, 2014 Published: December 10, 2014
Tylophorine compounds have been the focus of drug development for decades. Tylophorine derivatives exhibit anti-cancer activities but their cellular targets remain unknown. We used a biotinylated tylophorine derivative to probe for the interacting cellular target(s) of tylophorine. Tylophorine directly binds to caprin-1 and consequently enhances the recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA to form a ribonucleoprotein complex. Subsequently, this tylophorine targeted ribonucleoprotein complex is sequestered to the polysomal fractions and the protein expressions of the associated mRNA-transcripts are repressed. Caprin-1 depleted carcinoma cells become more resistant to tylophorine, associated with decreased formation of the ribonucleoprotein complex targeted by tylophorine. Consequently, tylophorine downregulates c-Myc and cyclins D1/D2, causing hypophosphorylation of Rb and suppression of both processing-body formation and the Warburg effect. Gene expression profiling and gain-of-c-Myc-function experiments also revealed that the downregulated c-Myc contributes to the anti-oncogenic effects of tylophorine compounds. 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 complex.
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