title: 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.
abstract: 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.
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.|Graduate Program of Biotechnology in Medicine, Institute of Molecular & Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors: Ya-Qi
authors: YQ
authors: Qiu
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors: Cheng-Wei
authors: CW
authors: Yang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors: Yue-Zhi
authors: YZ
authors: Lee
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Ruey-Bing
authors: RB
authors: Yang
authors: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Chih-Hao
authors: CH
authors: Lee
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors: Hsing-Yu
authors: HY
authors: Hsu
authors: Graduate Program of Biotechnology in Medicine, Institute of Molecular & Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors: Chien-Chung
authors: CC
authors: Chang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors: Shiow-Ju
authors: SJ
authors: Lee
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D020365:RNA Helicases; D034622:RNA Interference; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; C486562:CAPRIN1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D007212:Indolizines; D046912:Multiprotein Complexes; D010616:Phenanthrenes; D000075223:Poly-ADP-Ribose Binding Proteins; D020598:Proto-Oncogene Proteins c-myb; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; C004218:tylophorine