Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy
| Autor: | Ser Mei Koh, Shu Hui Neo, Lu Zheng, Xuezhi Bi, Qiao Jing Lew, Sheng-Hao Chao |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
p53
0301 basic medicine Transcription Genetic Blotting Western NPM Fluorescent Antibody Technique Apoptosis Breast Neoplasms Peptide P-TEFb 03 medical and health sciences HEXIM1 Ubiquitin Tumor Cells Cultured Humans Medicine Cytotoxic T cell Caspase Cell Proliferation chemistry.chemical_classification Nucleophosmin biology business.industry Cell growth RNA-Binding Proteins Molecular biology Peptide Fragments 030104 developmental biology KLA Oncology chemistry biology.protein Female Tumor Suppressor Protein p53 business Transcription Factors Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Shu Hui Neo 1 , Qiao Jing Lew 1 , Ser Mei Koh 2 , Lu Zheng 3 , Xuezhi Bi 3 , Sheng-Hao Chao 1, 4 1 Expression Engineering and Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668 2 Temasek Polytechnic, Singapore 529757 3 Proteomics Groups, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138668 4 Department of Microbiology, National University of Singapore, Singapore 117597 Correspondence to: Sheng-Hao Chao, e-mail: jimmy_chao@bti.a-star.edu.sg Keywords: HEXIM1, NPM, KLA, P-TEFb, p53 Received: June 18, 2015 Accepted: December 08, 2015 Published: December 29, 2015 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. |
| Databáze: | OpenAIRE |
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