title: Chemoresistant lung cancer stem cells display high DNA repair capability to remove cisplatin-induced DNA damage.
abstract: The persistence of lung cancer stem cells (LCSCs) has been proposed to be the main factor responsible for the recurrence of lung cancer as they are highly resistant to conventional chemotherapy. However, the underlying mechanisms are still unclear.
  
  
  
  We examined the cellular response of a human LCSC line to treatment with cisplatin, a DNA-damaging anticancer drug that is used extensively in the clinic. We compared the response to cisplatin of LCSCs and differentiated LCSCs (dLCSCs) by determining the viability of these cells, and their ability to accumulate cisplatin and to implement genomic and transcription-coupled DNA repair. We also investigated the transcription profiles of genes related to drug transport and DNA repair.
  
  
  
  LCSCs were found to be more stem-like, and more resistant to cisplatin-induced cytotoxicity than dLCSCs, confirming their drug resistance properties. LCSCs accumulated less cisplatin intracellularly than dLCSCs and showed less DNA damage, potentially due to their ability to down-regulate AQP2 and CTR1. The results of the transcription-coupled repair of cisplatin-DNA cross-links indicated a higher level of repair of DNA damage in LCSCs than in dLCSCs. In addition, LCSCs showed a greater ability to repair cisplatin-DNA interstrand cross-links than dLCSCs; this involved the activation of various DNA repair pathways.
  
  
  
  Our results further clarify the mechanism of cisplatin resistance in LCSCs in terms of reduced cisplatin uptake and enhanced ability to implement DNA repairs. These findings may aid in the design of the next-generation of platinum-based anticancer drugs.
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Wai-Kin
authors.initials: WK
authors.lastname: Yu
authors.affiliation: Shenzhen Key Laboratory of Biochip Research, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.|Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.|Shenzhen Key Laboratory of Biochip Research, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
authors.forename: Chi-Chun
authors.initials: CC
authors.lastname: Fong
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Yau Ma Tei, Hong Kong.
authors.forename: Tak-Chun
authors.initials: TC
authors.lastname: Yip
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Yau Ma Tei, Hong Kong.
authors.forename: Siu-Kie
authors.initials: SK
authors.lastname: Au
authors.affiliation: Shenzhen Key Laboratory of Biochip Research, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.|Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.|Shenzhen Key Laboratory of Biochip Research, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
authors.forename: Mengsu
authors.initials: M
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin