A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition

Amit Subedi; Makoto Muroi; Yushi Futamura; Tatsuro Kawamura; Harumi Aono; Mayuko Nishi; Akihide Ryo; Nobumoto Watanabe; Hiroyuki Osada

doi:10.1002/1873-3468.13361

A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition

Amit Subedi, Makoto Muroi, Yushi Futamura, Tatsuro Kawamura, Harumi Aono, Mayuko Nishi, Akihide Ryo, Nobumoto Watanabe^*, Hiroyuki Osada

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

Differences in the metabolism of cancer cells or cancer stem cells (CSCs) as compared to normal cells have provided avenues to safely target cancers. To discover metabolic inhibitors of CSCs, we performed alkaline phosphatase- and tumoursphere-based drug screening using induced cancer stem cell-like cells. From the screening of a RIKEN NPDepo chemical library, we discovered NPD2381 as a novel and selective cancer-stemness inhibitor that targets mitochondrial metabolism. Using our ChemProteoBase profiling, we found that NPD2381 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.

Original language	English
Pages (from-to)	763-776
Number of pages	14
Journal	FEBS Letters
Volume	593
Issue number	8
DOIs	https://doi.org/10.1002/1873-3468.13361
Publication status	Published - 2019 Apr
Externally published	Yes

Keywords

cancer metabolism
cancer stem cells
drug screen
mitochondrial inhibitors
serine biosynthesis
tumourspheres

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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title = "A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition",

abstract = "Differences in the metabolism of cancer cells or cancer stem cells (CSCs) as compared to normal cells have provided avenues to safely target cancers. To discover metabolic inhibitors of CSCs, we performed alkaline phosphatase- and tumoursphere-based drug screening using induced cancer stem cell-like cells. From the screening of a RIKEN NPDepo chemical library, we discovered NPD2381 as a novel and selective cancer-stemness inhibitor that targets mitochondrial metabolism. Using our ChemProteoBase profiling, we found that NPD2381 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.",

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author = "Amit Subedi and Makoto Muroi and Yushi Futamura and Tatsuro Kawamura and Harumi Aono and Mayuko Nishi and Akihide Ryo and Nobumoto Watanabe and Hiroyuki Osada",

note = "Funding Information: We thank members of the RIKEN NPDepo group for providing the chemical libraries, Miho Tanaka (RIKEN) for ChemProteome analysis, Toshihiko Nogawa (RIKEN) for LC/MS analysis, Takehiro Suzuki and Naoshi Dohmae (RIKEN) for protein identification by MS analysis, and Noriko Ikawa (Yokohama City University School of Medicine) for assistance in drug screening. The metabolome analysis was supported by the Japan Agency for Medical Research and Development (AMED). This work was supported in part by JSPS KAKENHI Grant Numbers JP16H06276, JP17H06412, JP18H03945, JP17K07783, and AMED Grant Number JP18cm0106112. Publisher Copyright: {\textcopyright} 2019 Federation of European Biochemical Societies",

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doi = "10.1002/1873-3468.13361",

language = "English",

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AU - Subedi, Amit

AU - Muroi, Makoto

AU - Futamura, Yushi

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AU - Aono, Harumi

AU - Nishi, Mayuko

AU - Ryo, Akihide

AU - Watanabe, Nobumoto

AU - Osada, Hiroyuki

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PY - 2019/4

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A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition

Abstract

Keywords

ASJC Scopus subject areas

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