Reduced SLC27A2 Induces Cisplatin Resistance in Lung Cancer Stem Cells by Negatively Regulating Bmi1-ABCG2 Signaling

摘要

Platinum-based chemotherapies have long been used as a standard treatment in non-small cell lung cancer (NSCLC). However, cisplatin resistance is a major problem that restricts the use of cisplatin. Lung cancer stem cells (LCSCs) represent a subpopulation that is responsible for chemo-resistance. We aim to investigate the biological function of SLC27A2 and its underlying mechanisms in regulating chemo-resistance to cisplatin in LCSCs. Here, our findings testified that CD166(+) cells which were derived from fresh primary NSCLC samples displayed stem cell-like features and were resistant to chemotherapy drug cisplatin. In patient cohort, we found the presence of a variable fraction of CD166(+) cells in 24 out of 25 primary NSCLC samples. Significantly, SLC27A2 expression was reduced in CD166(+) LCSCs. Reduced SLC27A2 correlated chemo-response and poor patient survival. Our results indicated that enhanced SLC27A2 expression sensitized CD166(+) LCSCs to cisplatin by in vitro and in vivo experiments. Microarray profiling showed that the expression of Bmi1 and ABCG2 was enhanced in p-SLC27A2-LCSCs compared with that in pc3.1DNA-LCSCs. Furthermore, we demonstrated that reduced SLC27A2 induced chemo-resistance in CD166(+) LCSCs by negatively regulating Bmi1-ABCG2 signaling, and ABCG2 was a direct transcriptional target of Bmi1. Thus, this study widens the window for identification and targeting of a cisplatin-resistant population and contributes to the development of potential therapeutics to improve the current treatment modalities in NSCLC. (C) 2015 Wiley Periodicals, Inc.