Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors
| Autor: | Hidehisa Iwata, Ryutaro Adachi, Osamu Kurasawa, Tomohiro Kawamoto, Osamu Sano, Ken-ichi Kazetani |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Necrosis Biology General Biochemistry Genetics and Molecular Biology necrosis law.invention Serine 03 medical and health sciences 0302 clinical medicine law medicine Transferase Research Articles chemistry.chemical_classification COX‐2 Drug discovery serine palmitoyl transferase Anticancer mechanism 030104 developmental biology Enzyme Biochemistry chemistry biologically annotated library 030220 oncology & carcinogenesis Suppressor combination screening medicine.symptom Research Article |
| Zdroj: | FEBS Open Bio |
| ISSN: | 2211-5463 |
| Popis: | Mechanistic understanding is crucial to anti-cancer drug discovery. Here, we reveal that inhibition of serine palmitoyl transferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, induced death in a lung cancer cell line via a necrosis-dependent pathway. To elucidate the mechanism of cell death induced by SPT inhibition,. a biologically annotated library of diverse compounds was screened with an SPT inhibitor. This analysis identified suppressors of SPT inhibitor-mediated cell death. Further analysis using hit compounds from this screening revealed that SPT inhibitors induce COX-2 expression, leading to necrosis-dependent cell death. SPT inhibitors might therefore represent novel candidates for cancer therapy via necrosis pathway regulation. Our data illustrates that compound combination screening of biologically annotated libraries could be used for mechanistic elucidation. |
| Databáze: | OpenAIRE |
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