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C6‐pyridinium ceramide induces Bax translocation from cytosol to mitochondria in MCF‐7 cells via a new signaling pathway
Author(s) -
Hou Qi,
Zhou Hui,
Novgordov Sergei,
Bielawska alicja,
Szulc Zdzislaw,
Obeid Lina,
Hannun Yusuf,
Hsu YiTe
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a507-c
Subject(s) - microbiology and biotechnology , mitochondrion , chromosomal translocation , cytosol , ceramide , apoptosis , signal transduction , staurosporine , caspase , chemistry , intermembrane space , biology , programmed cell death , protein kinase c , biochemistry , bacterial outer membrane , gene , enzyme , escherichia coli
Bax translocation from cytosol to mitochondria culminates a key step in cellular apoptosis. Currently, two main signaling pathways have been identified in the regulation of this translocation process. In one signaling pathway, such as that of TNFa, caspase‐8 cleavage of Bid results in the recruitment of Bax to mitochondria. However, in other signaling pathways, such as those of staurosporine and menadione, Bax translocation is regulated by a yet unidentified mechanism that is both caspase and Bid independent. Ceramide has been shown to be an important inducer of apoptosis that could trigger Bax conformational change and translocation to mitochondria. In this report, using a MCF‐7 cell line that stably expresses GFP‐tagged Bax, we have examined the regulation of Bax activation by the mitochondria‐targeting C6‐pyridinium ceramide, a new anti‐cancer agent. We found that this compound induced Bax translocation to mitochondria and promoted the release of cytochrome c and the loss of mitochondrial membrane potential. Like TNFa, C6‐pyridinium ceramide‐mediated Bax translocation is caspase‐dependent, as pan‐caspase inhibitor zVAD‐fmk could significantly inhibit this process. However, unlike TNFa, this translocation is not associated with Bid cleavage and co‐localization to mitochondria. In conclusion, we have identified a new Bax regulatory pathway that is caspase dependent and Bid independent.