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Journal of Lipid Research, Vol. 50, 2389-2397, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells

Junfei Jin^*,, Thomas D. Mullen, Qi Hou^*,**, Jacek Bielawski^*, Alicja Bielawska^*, Xiaoming Zhang^*, Lina M. Obeid^,, Yusuf A. Hannun^* and Yi-Te Hsu^1,*

^* Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
Research Center of Life Science, University of South China, Hengyang, Hunan 421001, P.R. China
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425
^** Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P.R. China
Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401

¹ To whom correspondence should be addressed. e-mail: hsuy{at}musc.edu

Compound C is commonly used as an inhibitor of AMP-activated protein kinase (AMPK), which serves as a key energy sensor in cells. In this study, we found that Compound C treatment of MCF7 cells led to Bax redistribution from the cytoplasm to mitochondria and cell death. However, this effect does not involve AMPK. In addition, we found that treatment with this compound leads to an enhanced ceramide production. Analyses by quantitative PCR and ceramide synthase activity assay suggest that ceramide synthase 5 (LASS/CerS 5) is involved in Compound C-induced ceramide upregulation. Downregulation of LASS/CerS 5 was found to attenuate Compound C-mediated ceramide production, Bax redistribution, and cell death.

Supplementary key words AMP-activated protein kinase signaling pathway • sphingolipid • cell death

Abbreviations: ACC, acetyl CoA carboxylase; AICAR, aminoimidazole-4-carboxamide riboside; AMPK, AMP-activated protein kinase; GFP, green fluorescent protein; LASS/CerS, longevity assurance homologue/ceramide synthase; MAPK, mitogen-activated protein kinase; qPCR, quantitative polymerase chain reaction; siRNA, small interfering RNA; t-BHQ, tert-butylhydroxyquinone

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