Reduced SLC27A2 induces cisplatin resistance in lung cancer stem cells by negatively regulating Bmi1‐ABCG2 signaling

Abstract

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. © 2015 Wiley Periodicals, Inc.

Targeting Lung Cancer Stem Cells: Research and Clinical Impacts

“…In addition, the enrichment of CSCs population were also reported in recent study, whereby the subpopulation of A549 and H2170 with markers CD166 + /EpCAM + showed higher expression upon cisplatin treatment as comparing to basal expression (99). In another study of NSCLC, the CD166 + cells with strong CSCs characteristics also were resistant when exposed to cisplatin drug (125). Furthermore, CSCs can adopt in quiescent state where it resist any cytotoxic insult (126) due to high expression of Bcl-2/Bcl-XL that function in mitochondrial ATP/ADP exchange as to prevent apoptosis which probably contributes to resistant of CSCs upon chemotherapy (127).…”

Stimulation of the hypoxia pathway modulates chemotherapy resistance in Hodgkin’s lymphoma cells

“…Ovarian cancer cells which were resistant against cisplatin showed also a lower expression of these both genes [51]. Su et al increased the expression of SLC27A2 in lung cancer stem cells and could sensitize these cells against cisplatin [52]. Changes in genes which regulated DNA repair pathways were not observed.…”

HSPA12B overexpression induces cisplatin resistance in non-small-cell lung cancer by regulating the PI3K/Akt/NF-κB signaling pathway

“…CDDP is a platinum chemotherapeutic agent and is widely used for the treatment of lung cancer (17). DNA is the primary target of CDDP; CDDP-induced DNA damage results in characteristic cellular changes, including the inhibition of DNA synthesis, suppression of RNA transcription, effects on the cell cycle, and the therapeutically beneficial process of apoptosis (16)(17)(18).…”