Abstract 2697: A novel therapeutic strategy to effectively kill CLL cells in stromal microenvironment by targeting lipid metabolism

Abstract

Abstract The tissue microenvironment promotes cancer cell survival and drug resistance, and thus presents a major challenge in cancer treatment. Recent study suggests that the microenvironmental protection of chronic lymphocytic leukemia (CLL) cells is particular important due to the unique metabolic properties of CLL cells. Emerging evidence suggests that altered fatty acid metabolism may be associated with the pathogenesis of CLL and could potentially provide a biochemical basis for targeting CLL. In the current study, we tested three classes of compounds that respectively inhibit the de novo fatty acids synthesis (FASN), block the transport of fatty acids from cytosol into mitochondria, or suppress fatty acid oxidation, for their ability to kill CLL cells in the presence and absence of bone marrow stromal cells. While all three inhibitors exhibited cytotoxic effect again CLL cells when the leukemia cells were culture alone, only the compound that inhibited the transport of fatty acids into mitochondria was highly effective in killing CLL in the presence of bone marrow stromal cells. Mechanistic study revealed that the cytotoxicity was not due to inhibition of ATP generation through mitochondrial β-oxidation of fatty acids, since there was no significant decrease in mitochondrial respiratory activity. We further showed that inhibition of FA transport into mitochondria suppressed biosynthesis of mitochondrial phospholipid, leading to a significant depletion of cardiolipin (CL), which is essential for maintaining mitochondrial membrane integrity. Depletion of CL by the FA transport inhibitor in CLL cells resulted in mitochondrial depolarization, release of cytochrome c, and massive apoptosis. Since this cell death process was through the intrinsic pathway and could not be rescued by the stromal environment, this might explain why inhibition of FA transport into the mitochondrial was highly effective in killing CLL cells in the presence of stromal cells. Importantly, we found that inhibition of FA transport had low toxicity in normal lymphocytes and stromal cells, suggesting that the normal cells might be less dependent on FA transport for cardiolipin biosynthesis. In summary, our study suggests that inhibition of FA transport into the mitochondria is a novel therapeutic strategy to effectively and selectively kill CLL cells in stromal microenvironment, and may potentially improve the clinical outcome of CLL treatment. Citation Format: Panpan Liu, Jinyun Liu, Marcia A. Ogasawara, Helene Pelicano, Ruihua Xu, Michael J. Keating, Peng Huang. A novel therapeutic strategy to effectively kill CLL cells in stromal microenvironment by targeting lipid metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2014-2697