Limits...
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.

Qiu YQ, Yang CW, Lee YZ, Yang RB, Lee CH, Hsu HY, Chang CC, Lee SJ - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.

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.

Show MeSH

Related in: MedlinePlus

A summary scheme for tylophorine-targeted anti-cancer pathwaysThe solid lines indicate the direct targeting of tylophorine compounds to caprin-1, c-Myc, and the related pathways. The dashed lines indicate the previously published c-Jun-mediated anti-cancer mechanism of tylophorine[25] including the results shown in Supplemental Figure 2 for decreased PTEN. The elevation of c-Jun by tylophorine compounds is not affected by ectopically overexpressed c-Myc as shown in Supplemental Figure 3 indicating that the tylophorine compounds target the caprin-1 and c-Myc mRNA-containing RNP complexes in parallel with their effects on c-Jun accumulation to elicit anti-cancer activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385842&req=5

Figure 7: A summary scheme for tylophorine-targeted anti-cancer pathwaysThe solid lines indicate the direct targeting of tylophorine compounds to caprin-1, c-Myc, and the related pathways. The dashed lines indicate the previously published c-Jun-mediated anti-cancer mechanism of tylophorine[25] including the results shown in Supplemental Figure 2 for decreased PTEN. The elevation of c-Jun by tylophorine compounds is not affected by ectopically overexpressed c-Myc as shown in Supplemental Figure 3 indicating that the tylophorine compounds target the caprin-1 and c-Myc mRNA-containing RNP complexes in parallel with their effects on c-Jun accumulation to elicit anti-cancer activity.

Mentions: In this study, 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). Because abnormal c-Myc signaling in cancer cells has been associated with oncogenicity, the downregulation of c-Myc by tylophorine compounds might play a significant role in the anti-cancer activity of these compounds.


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.

Qiu YQ, Yang CW, Lee YZ, Yang RB, Lee CH, Hsu HY, Chang CC, Lee SJ - Oncotarget (2015)

A summary scheme for tylophorine-targeted anti-cancer pathwaysThe solid lines indicate the direct targeting of tylophorine compounds to caprin-1, c-Myc, and the related pathways. The dashed lines indicate the previously published c-Jun-mediated anti-cancer mechanism of tylophorine[25] including the results shown in Supplemental Figure 2 for decreased PTEN. The elevation of c-Jun by tylophorine compounds is not affected by ectopically overexpressed c-Myc as shown in Supplemental Figure 3 indicating that the tylophorine compounds target the caprin-1 and c-Myc mRNA-containing RNP complexes in parallel with their effects on c-Jun accumulation to elicit anti-cancer activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385842&req=5

Figure 7: A summary scheme for tylophorine-targeted anti-cancer pathwaysThe solid lines indicate the direct targeting of tylophorine compounds to caprin-1, c-Myc, and the related pathways. The dashed lines indicate the previously published c-Jun-mediated anti-cancer mechanism of tylophorine[25] including the results shown in Supplemental Figure 2 for decreased PTEN. The elevation of c-Jun by tylophorine compounds is not affected by ectopically overexpressed c-Myc as shown in Supplemental Figure 3 indicating that the tylophorine compounds target the caprin-1 and c-Myc mRNA-containing RNP complexes in parallel with their effects on c-Jun accumulation to elicit anti-cancer activity.
Mentions: In this study, 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). Because abnormal c-Myc signaling in cancer cells has been associated with oncogenicity, the downregulation of c-Myc by tylophorine compounds might play a significant role in the anti-cancer activity of these compounds.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.

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.

Show MeSH
Related in: MedlinePlus