title: Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis.
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.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P R China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hou
authors.forename: Junfei
authors.initials: J
authors.lastname: Jin
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Novgorodov
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Yi-Te
authors.initials: YT
authors.lastname: Hsu
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C539200:2-N-(6'-(1''-pyridinium)hexanoyl)sphingosine; D000590:Amino Acid Chloromethyl Ketones; D002518:Ceramides; D006131:Growth Inhibitors; D011726:Pyridinium Compounds; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C101954:N-caproylsphingosine; D020169:Caspases