Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.6794
Title: Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy
Authors: Neo, S.H
Lew, Q.J
Koh, S.M
Zheng, L
Bi, X
Chao, S.-H 
Keywords: antineoplastic agent
caspase
cell penetrating peptide
hexamethylene bisacetamide inducible protein 1 basic region peptide
hybrid protein
nucleophosmin
positive transcription elongation factor b
protein p53
unclassified drug
HEXIM1 protein, human
peptide fragment
protein p53
RNA binding protein
TP53 protein, human
apoptosis
Article
breast cancer
cell killing
cellular distribution
controlled study
drug cytotoxicity
human
human cell
internalization
membrane depolarization
mitochondrial membrane potential
nucleolus
protein expression
antagonists and inhibitors
apoptosis
Breast Neoplasms
cell proliferation
female
fluorescent antibody technique
genetic transcription
genetics
metabolism
pathology
tumor cell culture
Western blotting
Apoptosis
Blotting, Western
Breast Neoplasms
Cell Proliferation
Female
Fluorescent Antibody Technique
Humans
Peptide Fragments
RNA-Binding Proteins
Transcription, Genetic
Tumor Cells, Cultured
Tumor Suppressor Protein p53
Issue Date: 2016
Citation: Neo, S.H, Lew, Q.J, Koh, S.M, Zheng, L, Bi, X, Chao, S.-H (2016). Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy. Oncotarget 7 (5) : 5483-5494. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.6794
Rights: Attribution 4.0 International
Abstract: Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb) and is recently identified as a novel positive regulator of p53. We previously showed the basic region (BR) of HEXIM1 mediates the binding of HEXIM1 to a nucleolar protein, nucleophosmin (NPM), and can be ubiquitinated by human double minute 2 protein. Here we identify a cytotoxic peptide derived from the BR of HEXIM1. When fused with a cell-penetrating peptide, the HEXIM1 BR peptide triggers rapid cytotoxic effect independent of p53. Similarly, when the BR peptide is linked with a breast cancer cell targeting peptide, LTV, the LTV-BR fusion peptide exhibits specific killing of breast cancer cells, which is not observed with the commonly used cytotoxic peptide, KLA. Importantly, the BR peptide fails to enter cells by itself and does not induce any cytotoxic effects when it is not guided by any cell-penetrating or cancer targeting peptides. We showed that HEXIM1 BR peptide depolarizes mitochondrial membrane potential in a p53-dependent manner and its cell-killing activity is not suppressed by caspase inhibition. Furthermore, we observed an accumulation of the internalized BR peptide in the nucleoli of treated cells and an altered localization of NPM. These results illustrate a novel mechanism which the BR peptide induces cell death and can potentially be used as a novel therapeutic strategy against breast cancer.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/180864
ISSN: 19492553
DOI: 10.18632/oncotarget.6794
Rights: Attribution 4.0 International
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