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.
Highlights
Caprin-1(Cytoplasmic activation- and proliferationassociated protein 1) is ubiquitously expressed, and its phosphorylation is required for normal cell cycle progression from the G1 to S phase
This caprin-1/G3BP1 complex is thought to regulate the transport and translation of mRNAs whose protein products are involved in proliferation and migration in multiple cell types because the carboxyl-terminal region of caprin-1 selectively binds to c-Myc or cyclin D2 mRNAs[13]
It was found that tylophorine compounds exert their anti-cancer activities via targeting the caprin-1, G3BP1, c-Myc mRNA, and cyclin D2 or D1 mRNAs containing RNP complex, inhibiting the functions of the RNP components and blocking the protein translation of the corresponding mRNA transcripts (e.g., c-Myc, cyclin D2, and cyclin D1, as well as their downstream pathway components such as pRb) (Fig. 7)
Summary
Caprin-1(Cytoplasmic activation- and proliferationassociated protein 1) is ubiquitously expressed, and its phosphorylation is required for normal cell cycle progression from the G1 to S phase. Caprin-1 co-localizes with G3BP1 (Ras GTPase-activating protein-binding protein 1) within the cytoplasmic RNA granules that are associated with microtubules This caprin-1/G3BP1 complex is thought to regulate the transport and translation of mRNAs whose protein products are involved in proliferation and migration in multiple cell types because the carboxyl-terminal region of caprin-1 selectively binds to c-Myc or cyclin D2 mRNAs[13]. The elucidation of the cellular targets of therapeutic natural products contributes to the identification of valuable novel drug targets for future development, and guides subsequent molecular pharmacology and mode-of-action studies[14, 16]. Several modes of action for anti-cancer tylophorine compounds have been reported[20, 25,26,27,28], their direct cellular target(s) and related pathways remain to be elucidated[24]. The identified cellular target(s) of tylophorine represent novel drug targets for anti-cancer therapeutic applications
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