Abstract 4601: Nisin, an apoptogenic bacteriocin, modulates oral cancer growth

Oral squamous cell carcinoma (OSCC) accounts for 50% of all oral malignancies and has a poor 5-year survival rate. Resistance to programmed cell death or apoptosis contributes to oral cancer progression and formation of aggressive tumors. Finding novel therapies that promote apoptosis is crucial for mitigating oral cancer. While bacteriocins, like nisin, prevent bacterial growth in foods, they have only recently been tested for prevention of cancer cell growth. Because nisin produces cell membrane pores, it changes ionic gradients within cells, leading to a net influx of calcium. This calcium increase may play a significant role in the induction of apoptosis and reduction in proliferation in cancer cells. We hypothesized that nisin, a bacteriocin and commonly used food preservative, has potential to serve as a novel therapeutic for treating OSCC. In vitro experiments to examine the effect of nisin on OSCC cells include: cell proliferation and apoptosis assays, immunoblotting, flow cytometry to determine cell cycle status, calcium influx assays, transfections to examine the mechanism of nisin9s effects. An orthotopic oral cancer mouse model was used to study the inhibitory effect of nisin on OSCC tumor growth in vivo. Nisin induces apoptosis and reduces proliferation of OSCC cells with a concomitant influx of extracellular calcium compared to primary oral keratinocytes. A concomitant influx of extracellular calcium and cell cycle arrest at the G2 check point followed nisin treatment. Nisin inhibited cell proliferation of OSCC cells by decreasing phosphorylation of cdc-2 and cyclin B, key modulators of the G2 phase of the cell cycle. In affymetrix gene array data, the most highly upregulated gene under nisin treatment conditions was ChaC1, a cation transport regulator activated by oxidized phospholipids that enhances apoptosis. Since nisin is known to preferentially interact with membrane phospholipids, ChaC1 is a likely nisin target. Nisin induces preferential apoptosis and decreased cell proliferation of OSCC cells compared to primary keratinocytes, likely due to differences in their membrane phospholipid composition that lead to greater increases in intracellular calcium and activation of ChaC1 in OSCC cells. Downregulation of Chac1 increased OSCC cell growth by increasing cdc-2 phosphorylation and cyclin B expression following nisin treatment. Mice tolerated high nisin doses well without compromising survival. Nisin administration reduced OSCC tumor burden in mice compared to double-distilled-water treated controls. These studies demonstrate that nisin suppresses OSCC cell and tumor growth in vitro and in vivo by promoting OSCC cell apoptosis, cell cycle arrest, and inhibiting cell proliferation. Increases in intracellular calcium potentially mediate this mechanism. These findings help establish baseline information regarding potential therapeutic use of nisin for OSCC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2011-4601