Cerulenin-mediated apoptosis is involved in adenine metabolic pathway.
Cerulenin, a fatty acid synthase (FAS) inhibitor, induces apoptosis of variety of tumor cells. To elucidate mode of action by cerulenin, we employed the proteomics approach using Schizosaccharomyces pombe. The differential protein expression profile of S. pombe revealed that cerulenin modulated the expressions of proteins involved in stresses and metabolism, including both ade10 and adk1 proteins. The nutrient supplementation assay demonstrated that cerulenin affected enzymatic steps transferring a phosphoribosyl group. This result suggests that cerulenin accumulates AMP and p-ribosyl-s-amino-imidazole carboxamide (AICAR) and reduces other necessary nucleotides, which induces feedback inhibition of enzymes and the transcriptional regulation of related genes in de novo and salvage adenine metabolic pathway. Furthermore, the deregulation of adenine nucleotide synthesis may interfere ribonucleotide reductase and cause defects in cell cycle progression and chromosome segregation. In conclusion, cerulenin induces apoptosis through deregulation of adenine nucleotide biosynthesis resulting in nuclear division defects in S. pombe.
Chung
Kyung-Sook
KS
Biopharmaceutical Division, KRIBB, 52 Oun-dong, Yusong-gu, Daejeon 305-806, Republic of Korea.
Sun
Nam-Kyu
NK
Lee
Seung-Hee
SH
Lee
Hyun-Jee
HJ
Choi
Shin-Jung
SJ
Kim
Sun-Kyung
SK
Song
Ju-Hyun
JH
Jang
Young-Joo
YJ
Song
Kyung-Bin
KB
Yoo
Hyang-Sook
HS
Simon
Julian
J
Won
Misun
M
D000225:Adenine / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002569:Cerulenin / Q000494:pharmacology*; D020090:Chromosome Segregation / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects; D015966:Gene Expression Regulation, Fungal; D040081:Protein Array Analysis; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000378:metabolism*
D002569:Cerulenin; D000225:Adenine