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      Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1

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          Nisin, a bacteriocin and commonly used food preservative, may serve as a novel potential therapeutic for treating head and neck squamous cell carcinoma (HNSCC), as it induces preferential apoptosis, cell cycle arrest, and reduces cell proliferation in HNSCC cells, compared with primary keratinocytes. Nisin also reduces HNSCC tumorigenesis in vivo. Mechanistically, nisin exerts these effects on HNSCC, in part, through CHAC1, a proapoptotic cation transport regulator, and through a concomitant CHAC1-independent influx of extracellular calcium. In addition, although CHAC1 is known as an apoptotic mediator, its effects on cancer cell apoptosis have not been examined. Our studies are the first to report CHAC1's new role in promoting cancer cell apoptosis under nisin treatment. These data support the concept that nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC, and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated.

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          Most cited references 30

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          Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity.

          Unlike numerous pore-forming amphiphilic peptide antibiotics, the lantibiotic nisin is active in nanomolar concentrations, which results from its ability to use the lipid-bound cell wall precursor lipid II as a docking molecule for subsequent pore formation. Here we use genetically engineered nisin variants to identify the structural requirements for the interaction of the peptide with lipid II. Mutations affecting the conformation of the N-terminal part of nisin comprising rings A through C, e.g. [S3T]nisin, led to reduced binding and increased the peptide concentration necessary for pore formation. The binding constant for the S3T mutant was 0.043 x 10(7) m(-1) compared with 2 x 10(7) m(-1) for the wild-type peptide, and the minimum concentration for pore formation increased from the 1 nm to the 50 nm range. In contrast, peptides mutated in the flexible hinge region, e.g. [DeltaN20/DeltaM21]nisin, were completely inactive in the pore formation assay, but were reduced to some extent in their in vivo activity. We found the remaining in vivo activity to result from the unaltered capacity of the mutated peptide to bind to lipid II and thus to inhibit its incorporation into the peptidoglycan network. Therefore, through interaction with the membrane-bound cell wall precursor lipid II, nisin inhibits peptidoglycan synthesis and forms highly specific pores. The combination of two killing mechanisms in one molecule potentiates antibiotic activity and results in nanomolar MIC values, a strategy that may well be worth considering for the construction of novel antibiotics.
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            Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic.

            Resistance to antibiotics is increasing in some groups of clinically important pathogens. For instance, high vancomycin resistance has emerged in enterococci. Promising alternative antibiotics are the peptide antibiotics, abundant in host defense systems, which kill their targets by permeabilizing the plasma membrane. These peptides generally do not act via specific receptors and are active in the micromolar range. Here it is shown that vancomycin and the antibacterial peptide nisin Z use the same target: the membrane-anchored cell wall precursor Lipid II. Nisin combines high affinity for Lipid II with its pore-forming ability, thus causing the peptide to be highly active (in the nanomolar range).
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              Calcium orchestrates apoptosis.


                Author and article information

                Cancer Med
                Cancer Med
                Cancer Medicine
                WILEY-VCH Verlag
                December 2012
                02 October 2012
                : 1
                : 3
                : 295-305
                Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry Ann Arbor, Michigan
                Author notes
                Yvonne L. Kapila, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Room 5223, Ann Arbor, MI 48109-1078. Tel: (734) 615-2295; Fax: (734) 763-5503; E-mail: ykapila@ 123456umich.edu

                Funding Information This work was supported by funding from National Institutes of Health (NIH) grant 3 P50 CA097248-07S1 and 2R56DE014429 to Y. L. K.

                © 2012 The Authors. Published by Blackwell Publishing Ltd.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Cancer Biology
                Original Research


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