DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells

Soo Yeon Chae, Dowoon Nam, Do Young Hyeon, Areum Hong, Timothy Dain Lee, Sujin Kim, Dongjoon Im, Jiwon Hong, Chaewon Kang, Ji Won Lee, Daehee Hwang, Sang Won Lee, Hugh I. Kim

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Neuroblastoma is a solid, heterogeneous pediatric tumor. Chemotherapy is widely used to treat neuroblastoma. However, dose-dependent responses and chemoresistance mechanisms of neuroblastoma cells to anticancer drugs remain challenging. Here, we investigated the dose-dependent effects of topotecan on human neuroblastoma cells (SK-N-SH, SH-SY5Y, and SK-N-BE) under various nutrient supply conditions. Serum-starved human neuroblastoma cells showed reduced toxicity. Their survival rate increased upon treatment with a high concentration (1 μM) of topotecan. Quantitative profiling of global and phosphoproteome identified 12,959 proteins and 48,812 phosphosites, respectively, from SK-N-SH cells. Network analysis revealed that topotecan upregulated DNA repair and cholesterol-mediated topotecan efflux, resulting in topotecan resistance. Results of DNA damage assay, cell cycle, and quantitative analyses of membrane cholesterol supported the validity of these resistance factors and their applicability to all neuroblastoma cells. Our results provide a model for high dose-dependent chemoresistance in neuroblastoma cells that could enable a patient-dependent chemotherapy screening strategy.

Original languageEnglish
Article number102325
JournaliScience
Volume24
Issue number4
DOIs
Publication statusPublished - 2021 Apr 23

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • Cancer
  • Molecular Biology
  • Proteomics

ASJC Scopus subject areas

  • General

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