Exploiting the TRIP-Br family of cell cycle regulatory proteins as chemotherapeutic drug targets in human cancer
Copyright policy )Exploiting the TRIP-Br family of cell cycle regulatory proteins as chemotherapeutic drug targets in human cancer
TRIP-Br1 and TRIP-Br2 are potent cell growth promoting factors that function as components of the E2F1/DP1 transcription complex to integrate positive growth signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. TRIP-Br1 has been demonstrated to be an oncogene. We recently reported that antagonism of the TRIP-Br integrator function by synthetic decoy peptides that compete with TRIP-Br for binding to PHD zinc finger- and/or bromodomain-containing proteins elicit an anti-proliferative effect and induces caspase-3-independent sub-diploidization in cancer cells in vitro. We now demonstrate the chemotherapeutic potential of TRIP-Br decoy peptides for the treatment of cutaneous and intracavitary lesions in vitro as well as in vivo in representative human nasopharyngeal cancer (CNE2), cervical cancer (Ca Ski) and melanoma (MeWo) cancer cell lines. In vitro, BrdU incorporation, colony formation assays and cell cycle analysis confirmed that TRIP-Br decoy peptides possess strong anti-proliferative effects and induce nuclear sub-diploidization in cancer cells. In vivo, CNE2, Ca Ski and MeWo-derived chick embryo chorioallantoic membrane (CAM) tumor xenografts were used to evaluate the effect of topically applied TRIP-Br peptides. Confocal microscopy and flow cytometric analysis demonstrated that cells comprising the tumor xenografts efficiently internalized topically applied FITC-labeled peptides. Fifty muM of TRIP-Br1 decoy peptide significantly suppressed the growth of NPC2-derived human nasopharyngeal tumors, while 50 muM of TRIP-Br2 decoy peptide significantly inhibited tumor growth in all three CAM tumor xenograft models. Two hundred muM of TRIP-Br1 decoy peptide significantly inhibited MeWo-derived tumors. These results suggest that the TRIP-Br integrator function may represent a novel chemotherapeutic target for the treatment of human cutaneous and intracavitary proliferative lesions.
- National University of Singapore Libraries Singapore
- National University of Singapore Singapore
Molecular therapy, 570, Chick embryo chorioallantoic membrane, Bromodomain, 610, Mice, Nude, Decoy peptide, Apoptosis, Chick Embryo, Mice, Cell cycle progression, Tumor Cells, Cultured, Animals, Humans, TRIP-Br, RNA, Small Interfering, Cell Proliferation, Homeodomain Proteins, Mice, Inbred BALB C, PHD zinc finger, Cell Cycle, Nuclear Proteins, Flow Cytometry, Tumor xenograft model, Xenograft Model Antitumor Assays, Peptide Fragments, Repressor Proteins, Gene transcription, Trans-Activators, Neoplasm, Female, Transcription Factors
Molecular therapy, 570, Chick embryo chorioallantoic membrane, Bromodomain, 610, Mice, Nude, Decoy peptide, Apoptosis, Chick Embryo, Mice, Cell cycle progression, Tumor Cells, Cultured, Animals, Humans, TRIP-Br, RNA, Small Interfering, Cell Proliferation, Homeodomain Proteins, Mice, Inbred BALB C, PHD zinc finger, Cell Cycle, Nuclear Proteins, Flow Cytometry, Tumor xenograft model, Xenograft Model Antitumor Assays, Peptide Fragments, Repressor Proteins, Gene transcription, Trans-Activators, Neoplasm, Female, Transcription Factors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).10 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
Citations provided by BIP!Popularity provided by BIP!