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

FEBS Lett. 2019 Apr;593(8):763-776. doi: 10.1002/1873-3468.13361. Epub 2019 Mar 23.


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.

Keywords: cancer metabolism; cancer stem cells; drug screen; mitochondrial inhibitors; serine biosynthesis; tumourspheres.

Publication types

  • Editorial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Glucose / metabolism
  • Humans
  • Metabolomics
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Serine / biosynthesis*


  • Antineoplastic Agents
  • Serine
  • Glucose