HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.

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.
AuthorsYa-Qi Qiu, Cheng-Wei Yang, Yue-Zhi Lee, Ruey-Bing Yang, Chih-Hao Lee, Hsing-Yu Hsu, Chien-Chung Chang, Shiow-Ju Lee
JournalOncotarget (Oncotarget) Vol. 6 Issue 4 Pg. 2148-63 (Feb 10 2015) ISSN: 1949-2553 [Electronic] United States
PMID25669982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: