Yu Wai-Kin, Wang Zhigang, Fong Chi-Chun, Liu Dandan, Yip Tak-Chun, Au Siu-Kie, Zhu Guangyu, Yang Mengsu
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.
Br J Pharmacol. 2017 Feb;174(4):302-313. doi: 10.1111/bph.13690. Epub 2017 Jan 16.
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.
肺癌干细胞（LCSCs）的持续存在被认为是肺癌复发的主要因素，因为它们对传统化疗具有高度抗性。然而，其潜在机制仍不清楚。
我们检测了一种人肺癌干细胞系对顺铂治疗的细胞反应，顺铂是一种临床上广泛使用的具有DNA损伤作用的抗癌药物。我们通过测定这些细胞的活力、积累顺铂的能力以及进行基因组和转录偶联DNA修复的能力，比较了肺癌干细胞（LCSCs）和分化的肺癌干细胞（dLCSCs）对顺铂的反应。我们还研究了与药物转运和DNA修复相关基因的转录谱。
发现肺癌干细胞比分化的肺癌干细胞更具干细胞样特性，对顺铂诱导的细胞毒性更具抗性，证实了它们的耐药特性。肺癌干细胞在细胞内积累的顺铂比分化的肺癌干细胞少，且DNA损伤较小，这可能是由于它们下调水通道蛋白2（AQP2）和铜转运蛋白1（CTR1）的能力。顺铂-DNA交联的转录偶联修复结果表明，肺癌干细胞中DNA损伤的修复水平高于分化的肺癌干细胞。此外，肺癌干细胞修复顺铂-DNA链间交联的能力比分化的肺癌干细胞更强；这涉及多种DNA修复途径的激活。
我们的结果从顺铂摄取减少和DNA修复能力增强方面进一步阐明了肺癌干细胞对顺铂耐药的机制。这些发现可能有助于下一代铂类抗癌药物的设计。
