Abstract
BackgroundThere is an urgent need for new approaches to deliver bioactive molecules to cancer cells efficiently and specifically.MethodsHere we fuse the cancer cell nuclear targeting module of the Chicken Anaemia Virus Apoptin protein to the core histones H2B and H3 and utilise them in transfection, protein transduction and DNA binding assays.ResultsWe found subsequent nuclear accumulation of these proteins to be 2–3 fold higher in tumour compared to normal cells in transfected isogenic human osteosarcoma and breast tumour progression models. This represents the first demonstration of enhanced nuclear targeting by Apoptin in a tumour progression model, and its functionality in a heterologous protein context. Excitingly, we found that the innate transduction ability of histones could be exploited in combination with the Apoptin nuclear targeting module to effect an overall 13-fold higher delivery of protein to osteosarcoma cancer cell nuclei compared to their isogenic normal counterparts.ConclusionsThis is the first report of cancer-cell specificity by a cell penetrating protein, with important implications for the use of protein transduction as a vehicle for gene/drug delivery in the future, and in particular in the development of highly specific and effective anti-cancer agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1045-z) contains supplementary material, which is available to authorized users.
Highlights
There is an urgent need for new approaches to deliver bioactive molecules to cancer cells efficiently and
The Apoptin tumour cell enhanced nuclear targeting signal (tNTS) confers tumour cell selectivity to histones H2B and H3 the Apoptin tNTS has been shown to be able to confer tumour-cell selective nuclear targeting onto heterologous proteins such as green fluorescent protein (GFP) [18,28], it has never been confirmed to confer tumour-cell selectivity to proteins that are intrinsically able to accumulate to high levels in the nucleus
We generated mammalian and bacterial expression vectors which contain a GFP moiety fused to the Nterminus of either histone H2B or H3 and which contain either the Apoptin tNTS or an optimised version of the SV40 large tumour antigen nuclear localisation signal (NLS) (Op-T-NLS) fused to their C-terminus
Summary
There is an urgent need for new approaches to deliver bioactive molecules to cancer cells efficiently and . The principal difficulty in achieving efficient anti-cancer treatment, whether by chemotherapy, radiotherapy or even excision surgery, has always been in administering the therapy to tumour cells without affecting healthy bystander cells [4,5,6,7,8]. A protein that has attracted interest in this context is viral protein 3 (VP3, known as Apoptin) from chicken anaemia virus (CAV), which shows enhanced nuclear targeting abilty in tumour compared to normal cells [9,10,11,12]. TNTS to confer cancer cell enhanced nuclear targeting with only minimal toxicity makes it an attractive targeting moiety because of this additional layer of safety by comparison with full length Apoptin. The Aptoptin tNTS is unique in terms of potential as the basis of cancer therapies targeting the nuclei of tumour cells [3,9]
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