Abstract
Platinum-based drugs are the firstline of treatment for non-small cell lung cancer (NSCLC), but resistance to these drugs is a major obstacle to effective chemotherapy. Our previous study revealed that the green tea polyphenol, EGCG, induced cisplatin transporter CTR1 (copper transporter 1) and enhanced cisplatin sensitivity in ovarian cancer. In this study, we found that EGCG upregulated CTR1 and increased platinum accumulation in NSCLC (A549, H460 and H1299) cells, cDDP-resistant A549 cells and a nude mouse xenograft model. Cisplatin-induced inhibition of cell growth was enhanced by EGCG treatment in vitro and in vivo. MicroRNA hsa-mir-98-5p appears to suppress CTR1 gene expression, while long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) appears to enhance it. Bioinformatics analysis showed that hsa-mir-98-5p has specific complementary binding sites for NEAT1. In addition, hsa-mir-98-5p was predicted to be a putative CTR1 target. NEAT1 may act as a competing endogenous lncRNA to upregulate EGCG-induced CTR1 by sponging hsa-mir-98-5p in NSCLC. Our findings reveal a novel mechanism how NEAT1 upregulates EGCG-induced CTR1 and enhances cisplatin sensitivity in vitro and in vivo, and suggest EGCG could serve as an effective adjuvant chemotherapeutic in lung cancer treatment.
Highlights
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide [1,2]
Our previous study demonstrated that the green tea polyphenol, EGCG, induced cDDP transporter CTR1 expression and enhanced cDDP sensitivity in ovarian cancer [14]
This is the first report to show that EGCGinduced CTR1 is regulated by hsa-mir-98-5p and nuclear enriched abundant transcript 1 (NEAT1) in non-small cell lung cancer (NSCLC) cells (Figure 7)
Summary
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide [1,2]. Platinum-based chemotherapy, such as cisplatin (cDDP), is a conventional treatment for most advanced NSCLC patients [3], but resistance to their therapeutics is a major obstacle. Platinum drug transportation (import and export) and retention in tumor cells are reportedly crucial factors in treatment efficacy [4,5]. Copper transporter 1 (CTR1, or hCtr encoded by SLC31A1), a copper influx transporter, reportedly promotes a significant fraction of cDDP internalization in tumor cells [7,8,9]. CDDP resistance in cancers is associated with changes in CTR1 level, sub-cellular localization or functionality [10,11]. As the primary copper influx transporter, CTR1 controls cellular cDDP accumulation. CTR1 upregulation can sensitize tumor cells to platinum drugs, while CTR1 downregulation promotes resistance [9]
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