Journal
JOURNAL OF LIPID RESEARCH
Volume 52, Issue 2, Pages 278-288Publisher
ELSEVIER
DOI: 10.1194/jlr.M012161
Keywords
ceramide; Bax; mitochondria
Categories
Funding
- National Institutes of Health [NS-40932, AG-16583]
- Office of Research and Development, US Department of Veterans Affairs
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C-6-pyridinium (D-erythro -2-N-[6'-(1 '' -pyridinium)hexanoyl]sphingosine bromide [LCL29]) is a cationic mitochondrion-targeting ceramide analog that promotes mitochondrial permeabilization and cancer cell death. In this study, we compared the biological effects of that compound with those of D -erythro-C-6-ceramide, its non-mitochondrion-targeting analog. In MCF7 cells it was found that C-6 -pyridinium ceramide preferentially promoted autophagosome formation and retarded cell growth more extensively than its uncharged analog. This preferential inhibition of cell growth was also observed in breast epithelial cells and other breast cancer cells. In addition, this compound could promote Bax translocation to mitochondria. This redistribution of Bax in MCF7 cells could be blocked by the pan-caspase inhibitor zVAD-fmk but via a Bid-independent signaling pathway. Moreover, C-6 -pyridinium ceramide-induced translocation of Bax to mitochondria led to mitochondrial permeabilization and cell death. Overall, we show that mitochondrial targeting of C-6 -pyridinium ceramide significantly enhances cellular response to this compound.-Hou, Q., J. Jin, H. Zhou, S. A. Novgorodov, A. Bielawska, Z. M. Szulc, Y. A. Hannun, L. M. Obeid, and Y-T. Hsu. Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J. Lipid Res. 2011. 52: 278-288.
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