Abstract 4675: Fatty acid metabolism is a possible target for treatment of cyclin D1 over-expressing mantle cell lymphoma
Authors: Michael A. Dengler, Matthias Gutekunst, Annette M. Staiger, Stephanie Kopacz, German Ott, Heiko van der Kuip, Walter E. Aulitzky
Journal: Cancer Research (2012)

Abstract Cyclin D1 over-expression has been linked to the development and progression of several types of cancer including mantle cell lymphoma (MCL), an aggressive type of B-cell lymphoma characterized by a t(11;14)(q13;q32) chromosomal translocation. Recent studies have shown that cyclin D1 is a multifunctional protein not only regulating the cell cycle but also affecting other cellular processes including DNA repair, apoptosis, as well as glucose, fatty acid, and lipid metabolism. In this study, we investigated the effects of the fatty acid synthase and lipase inhibitor Orlistat on cyclin D1 over-expressing MCL cell lines. In contrast to non-malignant peripheral blood lymphocytes and normal fibroblasts all MCL cell lines examined were sensitive to Orlistat. This enhanced sensitivity was dependent on cyclin D1 overexpression since siRNA mediated cyclin D1 knockdown almost completely rescued MCL cells from Orlistat induced apoptosis. Cell death upon Orlistat treatment was accompanied by loss of mitochondrial membrane potential and dependent on caspase activation since pre-incubation of the cells with the pan-caspase inhibitor zVAD-fmk completely blocked induction of apoptosis. We therefore investigated potential Orlistat-mediated changes in the expression levels of the pro- and anti-apoptotic Bcl-2 family proteins and found NOXA to be strongly induced whereas the expression of other Bcl-2 proteins did not change significantly. RNAi mediated knockdown of NOXA inhibited induction of cell death demonstrating the predominant role of this protein for the proapoptotic effect of Orlistat in MCL cells. Interestingly, silencing of cyclin D1 reduced the expression of NOXA upon Orlistat treatment further indicating a connection between cyclin D1, fatty acid metabolism, and the induction of NOXA. Since inhibition of fatty acid metabolism by Orlistat was found to disturb the balance between pro- and anti-apoptotic proteins in MCL cells we analyzed possible combinatory effects with Bcl-2 family modulators. Co-treatment of the cells with Orlistat and the BH3 mimetic ABT737 led to a rapid induction of cell death and an almost complete loss of cell viability in cyclin D1 over-expressing cells. A similar synergistic effect could be observed by combining Orlistat and 2-deoxy-D-glucose, a glycolysis inhibitor known to reduce MCL1 protein. These combinatory effects were selective for MCL cells as the same treatments had only minor or no effects on cell viability of primary PBMCs and fibroblasts from healthy donors. In summary, our results for the first time indicate that fatty acid metabolism may be an attractive target for therapy of cyclin D1 over-expressing MCL cells. Furthermore, these observations may contribute to the development of rational strategies combining fatty acid metabolism inhibitors with Bcl-2 family modulators for treatment of MCL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4675. doi:1538-7445.AM2012-4675