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
Affiliations
Soo Yeon Chae
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Dowoon Nam
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Do Young Hyeon
Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
Areum Hong
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
Timothy Dain Lee
Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
Sujin Kim
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Dongjoon Im
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Jiwon Hong
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Chaewon Kang
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
Ji Won Lee
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
Daehee Hwang
Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Corresponding author
Sang-Won Lee
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea; Corresponding author
Hugh I. Kim
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea; Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea; Corresponding author
Summary: 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.
