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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemistry
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Alkaloids / metabolism
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Alkaloids / pharmacology
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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cell Line, Tumor
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Cyclin D2 / genetics
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Cyclin D2 / metabolism
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DNA Helicases
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Indolizines / chemistry
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Indolizines / metabolism
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Indolizines / pharmacology
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MCF-7 Cells
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Mice
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / metabolism*
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Phenanthrenes / chemistry
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Phenanthrenes / metabolism
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Phenanthrenes / pharmacology
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Poly-ADP-Ribose Binding Proteins
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Protein Binding
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Proto-Oncogene Proteins c-myb / genetics
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Proto-Oncogene Proteins c-myb / metabolism*
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RNA Helicases
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RNA Interference
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RNA Recognition Motif Proteins
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism
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Tumor Burden / drug effects
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Tumor Burden / genetics
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U937 Cells
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Xenograft Model Antitumor Assays
Substances
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Alkaloids
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CAPRIN1 protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin D2
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Indolizines
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Multiprotein Complexes
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Phenanthrenes
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Poly-ADP-Ribose Binding Proteins
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Proto-Oncogene Proteins c-myb
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RNA Recognition Motif Proteins
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RNA, Messenger
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Ribonucleoproteins
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DNA Helicases
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G3BP1 protein, human
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RNA Helicases
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tylophorine