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.
Highlights
Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) was originally identified from vascular smooth muscle cells treated with hexamethylene bisacetamide (HMBA), an anti-proliferation compound [1]
Comparable cytotoxicity was observed in normal cells, including HEK293 cells and human foreskin fibroblasts (HFFs) (Figure 1C), suggesting the cytotoxic effect of basic region (BR) peptide occurs to all cell types once it is internalized into cells
We report the potential use of a novel cytotoxic peptide derived from the BR of HEXIM1
Summary
HEXIM1 was originally identified from vascular smooth muscle cells treated with hexamethylene bisacetamide (HMBA), an anti-proliferation compound [1]. HEXIM1 exhibits its anti-cancer effects through the inhibition of the ERα-dependent gene expression [8]. Our previous studies have demonstrated the functional interactions between HEXIM1 and other critical proteins involved in cancer, including the tumor suppressor p53, human double minute-2 protein (HDM2), and nucleophosmin (NPM). HEXIM1 directly binds to p53 and stabilizes p53 by blocking the HDM2-mediated ubiquitination of p53. HEXIM1 is required for p53 activation induced by anti-cancer drugs/compounds [9, 10]. The HDM2ubiquitinated HEXIM1 exhibits a stronger inhibition www.impactjournals.com/oncotarget in P-TEFb-dependent transcription [11]. NPMc+ is found to interact and sequester a portion of HEXIM1 in the cytoplasm of the NPMc+ AML cell line and activates P-TEFb-dependent transcription, suggesting the involvement of HEXIM1 in tumorigenesis of AML [17]
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