A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition
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- Amit Subedi
- Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Japan
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- Makoto Muroi
- Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Japan
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- Yushi Futamura
- Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Japan
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- Tatsuro Kawamura
- RIKEN‐Max Planck Joint Research Division for Systems Chemical Biology RIKEN Center for Sustainable Resource Science Wako Japan
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- Harumi Aono
- Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Japan
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- Mayuko Nishi
- Department of Microbiology Yokohama City University School of Medicine Japan
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- Akihide Ryo
- Department of Microbiology Yokohama City University School of Medicine Japan
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- Nobumoto Watanabe
- RIKEN‐Max Planck Joint Research Division for Systems Chemical Biology RIKEN Center for Sustainable Resource Science Wako Japan
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- Hiroyuki Osada
- Chemical Biology Research Group RIKEN Center for Sustainable Resource Science Wako Japan
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説明
<jats:p>Differences in the metabolism of cancer cells or cancer stem cells (<jats:styled-content style="fixed-case">CSC</jats:styled-content>s) as compared to normal cells have provided avenues to safely target cancers. To discover metabolic inhibitors of <jats:styled-content style="fixed-case">CSC</jats:styled-content>s, we performed alkaline phosphatase‐ and tumoursphere‐based drug screening using induced cancer stem cell‐like cells. From the screening of a <jats:styled-content style="fixed-case">RIKEN NPD</jats:styled-content>epo chemical library, we discovered <jats:styled-content style="fixed-case">NPD</jats:styled-content>2381 as a novel and selective cancer‐stemness inhibitor that targets mitochondrial metabolism. Using our ChemProteoBase profiling, we found that <jats:styled-content style="fixed-case">NPD</jats:styled-content>2381 increases the expression of enzymes within the serine biosynthesis pathway. We also found a role for serine in protecting cancer cells from mitochondrial inhibitors. Our results suggest the existence of a compensatory mechanism to increase the level of intracellular serine in response to mitochondrial inhibitors.</jats:p>
収録刊行物
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- FEBS Letters
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FEBS Letters 593 (8), 763-776, 2019-03-23
Wiley