@article{2701d6448f9f4caa9ecdf607589be32f,
title = "DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells",
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.",
keywords = "Cancer, Molecular Biology, Proteomics",
author = "Chae, {Soo Yeon} and Dowoon Nam and Hyeon, {Do Young} and Areum Hong and Lee, {Timothy Dain} and Sujin Kim and Dongjoon Im and Jiwon Hong and Chaewon Kang and Lee, {Ji Won} and Daehee Hwang and Lee, {Sang Won} and Kim, {Hugh I.}",
note = "Funding Information: This work was supported by the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) grant funded by the Korea government (Ministry of Education) (2019R1A6C1010028 and 2020R1A6C103A027) and the Collaborative Genome Program for Fostering New Post-Genome Industry (NRF-2017M3C9A5031597) of the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning. This work was also supported by the NRF of Korea (2019R1A2C2086193), the National Research Council of Science and Technology of Korea (CRC-15-04-KIST), and the Korea University Future Research Grant. We acknowledge the KBSI for confocal measurements. H.I.K thanks Prof. Min-Sik Kim at Daegu Gyeongbuk Institute of Science & Technology (DGIST) for the critical discussion of the manuscript. S.Y.C. D.N. A.H. D.I. J.H. C.K. and S.K. conducted the experiments. S.Y.C. A.H. H.I.K. S.-W.L. and D.H. designed the experiments. S.Y.C. D.Y. H. A.H. T.D.L. and D.N. analyzed the data. S.Y.C. D.Y. H. D.N. A.H. J.W.L. H.I.K. S.-W.L. and D.H. wrote the paper. The authors declare no competing financial interests. Funding Information: This work was supported by the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) grant funded by the Korea government (Ministry of Education) ( 2019R1A6C1010028 and 2020R1A6C103A027 ) and the Collaborative Genome Program for Fostering New Post-Genome Industry ( NRF-2017M3C9A5031597 ) of the National Research Foundation of Korea (NRF) , funded by the Ministry of Science, ICT, and Future Planning . This work was also supported by the NRF of Korea ( 2019R1A2C2086193 ), the National Research Council of Science and Technology of Korea ( CRC-15-04-KIST ), and the Korea University Future Research Grant. We acknowledge the KBSI for confocal measurements. H.I.K thanks Prof. Min-Sik Kim at Daegu Gyeongbuk Institute of Science & Technology (DGIST) for the critical discussion of the manuscript. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = apr,
day = "23",
doi = "10.1016/j.isci.2021.102325",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}
