Abstract B47: Exploring the mechanism of cancer stem cell-specific action by salinomycin in yeast as a model

Abstract

Abstract The antibiotic salinomycin represents a selective potassium ionophore. It has recently attracted considerable attention due to its stem-cell specific mode of action as elucidated in a breast cancer stem cell model [1]. Further studies revealed additional benefits, e.g. the triggering of apoptosis in resistant cancer cell lines and reversal of multidrug resistance [2,3]. In budding yeast, we discovered that this agent is active and, similar to nigericin, prominently causes mitochondrial damage as revealed by the emergence of respiration-defective cells. We also noted the frequent occurrence of salinomycin-resistant clones which may prove to be an obstacle in chemotherapy. We used the collection of systematic gene deletions in haploid yeast to characterize genes whose deletion confers sensitivity or resistance to salinomycin if a carbon source is provided (glycerol) that requires active respiration for growth. With this toxicogenomics approach in a model organism, we attempt to elucidate cancer stem cell-specific therapy targets and suggest strategies to avoid the development of salinomycin resistance. Among salinomycin-sensitive deletion mutants, significant overlap was found with known mutants sensitive to the ionophore monensin. Within this group, mutants that compromise vacuole/Golgi function and autophagy dominate. Novel genes were also uncovered which confer salinomycin sensitivity if deleted, such as CAJ1, encoding a heat shock protein of the dnaJ family, and certain arginine synthesis genes. On the other hand, deletions of TOR pathway components as well as deletions of the E2-ubiquitin conjugating enzymes UBC13 and MMS2 were among the most salinomycin-resistant mutants we found. In almost all cases, a strong correlation between salinomycin and nigericin sensitivity was observed. Since salinomycin appears to be the more efficient anti-cancer stem cell agent [1], the few cases of differential sensitivity will be discussed. [1] Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, et al. (2009) Cell 138:645–659. [2] Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C (2009) Biochem Biophys Res Commun 390:743–749. [3]Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C (2010) Biochem Biophys Res Commun 394:1098–1104. Supported by Cancer Prevention and Research Institute of Texas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B47.