Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis

Hui Zhou,Sergei A. Novgorodov,Yusuf A. Hannun,Junfei Jin,Alicja Bielawska,Qi Hou,Yi-Te Hsu,Lina M. Obeid,Zdzislaw M. Szulc

doi:10.1194/jlr.m012161

Abstract

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.

Highlights

C6-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
These results indicate that C6-pyridinium ceramidemediated Bax translocation to mitochondria in MCF7 cells is dependent on a caspase but independent of Bid
C6-pyridinium ceramide treatment of MCF7 cells significantly enhanced the production of acidic vesicular organelles and autophagosomes and elevated the level of LC3-II

Summary

Introduction

C6-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 MCF7 cells it was found that C6-pyridinium ceramide preferentially promoted autophagosome formation and retarded cell growth more extensively than its uncharged analog. This preferential inhibition of cell growth was observed in breast epithelial cells and other breast cancer cells. This compound could promote Bax translocation to mitochondria. C6-pyridinium ceramide-induced translocation of Bax to mitochondria led to mitochondrial permeabilization and cell death. Hsu. Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies

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