title: Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy.
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.
authors.affiliation: Expression Engineering and Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668.
authors.forename: Shu Hui
authors.initials: SH
authors.lastname: Neo
authors.affiliation: Expression Engineering and Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668.
authors.forename: Qiao Jing
authors.initials: QJ
authors.lastname: Lew
authors.affiliation: Temasek Polytechnic, Singapore 529757.
authors.forename: Ser Mei
authors.initials: SM
authors.lastname: Koh
authors.affiliation: Proteomics Groups, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Proteomics Groups, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668.
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Bi
authors.affiliation: Expression Engineering and Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668.|Department of Microbiology, National University of Singapore, Singapore 117597.
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Chao
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C476123:HEXIM1 protein, human; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: HEXIM1; KLA; NPM; P-TEFb; p53