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.
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Authors | Ya-Qi Qiu, Cheng-Wei Yang, Yue-Zhi Lee, Ruey-Bing Yang, Chih-Hao Lee, Hsing-Yu Hsu, Chien-Chung Chang, Shiow-Ju Lee |
Journal | Oncotarget
(Oncotarget)
Vol. 6
Issue 4
Pg. 2148-63
(Feb 10 2015)
ISSN: 1949-2553 [Electronic] United States |
PMID | 25669982
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Alkaloids
- CAPRIN1 protein, human
- Carrier Proteins
- Cell Cycle Proteins
- Cyclin D2
- Indolizines
- Multiprotein Complexes
- Phenanthrenes
- Poly-ADP-Ribose Binding Proteins
- Proto-Oncogene Proteins c-myb
- RNA Recognition Motif Proteins
- RNA, Messenger
- Ribonucleoproteins
- DNA Helicases
- G3BP1 protein, human
- RNA Helicases
- tylophorine
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Topics |
- Alkaloids
(chemistry, metabolism, pharmacology)
- Animals
- Blotting, Western
- Carrier Proteins
(genetics, metabolism)
- Cell Cycle Proteins
(genetics, metabolism)
- Cell Line
- Cell Line, Tumor
- Cyclin D2
(genetics, metabolism)
- DNA Helicases
- HEK293 Cells
- HeLa Cells
- Hep G2 Cells
- Humans
- Indolizines
(chemistry, metabolism, pharmacology)
- MCF-7 Cells
- Mice
- Multiprotein Complexes
(genetics, metabolism)
- Neoplasms
(drug therapy, genetics, metabolism)
- Phenanthrenes
(chemistry, metabolism, pharmacology)
- Poly-ADP-Ribose Binding Proteins
- Protein Binding
- Proto-Oncogene Proteins c-myb
(genetics, metabolism)
- RNA Helicases
- RNA Interference
- RNA Recognition Motif Proteins
- RNA, Messenger
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Ribonucleoproteins
(genetics, metabolism)
- Tumor Burden
(drug effects, genetics)
- U937 Cells
- Xenograft Model Antitumor Assays
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