期刊
ONCOTARGET
卷 6, 期 4, 页码 2148-2163出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3236
关键词
Caprin-1; c-Myc; Cyclin D; G3BP1; Processing Body
资金
- National Science Council of Taiwan [NSC 102-2628-B-400-002-MY3]
- National Health Research Institutes, Taiwan, R.O.C.
- Ministry of Economic Affairs, R.O.C. [102-EC-17-A-02-04-1099, 103-EC-17-A-22-1099]
- National Health Research Institutes
- National Tsing Hua University
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 anticancer activity predominantly by targeting and sequestering the caprin-1 protein and c-Myc mRNA associated ribonucleoprotein complex.
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