Abstract
Flap endonuclease 1 (FEN1) overexpression promotes breast cancer. We investigated the role of FEN1 in cisplatin resistance and the chemosensitizing effects of curcumin in breast cancer cells. We demonstrated that FEN1 overexpression promotes cisplatin resistance in breast cancer cells, and that FEN1 knockdown enhances cisplatin sensitivity. Curcumin down-regulated FEN1 expression in a dose-dependent manner. A combination of cisplatin and curcumin enhanced breast cancer cell sensitivity to cisplatin by down-regulating FEN1 expression in vitro and in vivo. Increased ERK phosphorylation contributed to cisplatin resistance and cisplatin-induced FEN1 overexpression in breast cancer cells. Inhibiting ERK phosphorylation stimulated the chemosensitizing effect of curcumin to cisplatin by targeting FEN1. These data reveal that FEN1 overexpression promotes cisplatin resistance, and suggest FEN1 could be a potential therapeutic target to relieve cisplatin resistance in breast cancer. We also demonstrated that curcumin sensitizes breast cancer cells to cisplatin through FEN1 down-regulation.
Highlights
Cisplatin is a powerful antineoplastic drug that treats solid tumors, including head and neck, lung, testis, ovary, and breast cancers [1, 2]
When MCF-7 cells were treated with 2 μg/mL cisplatin alone or combined with 20 μmol/L of curcumin, and MCF-7DDP cells were treated with 5 μg/mL cisplatin alone or combined with 30 μmol/L of curcumin (Figure 7C), ERK phosphorylation and Flap endonuclease 1 (FEN1) expression levels were decreased in the combination treatment group compared with the cisplatin alone treatment group
The DNA repair mechanism involved in cisplatin resistance mainly includes nucleotide-excision repair, mismatch repair, and base excision repair
Summary
Cisplatin (cis-diammedichloroplatinum, DDP) is a powerful antineoplastic drug that treats solid tumors, including head and neck, lung, testis, ovary, and breast cancers [1, 2]. Cisplatin resistance frequently occurs in patients, which offsets the cisplatin-induced inhibited DNA repair. Structurespecific nuclease family members repair DNA damage by removing damaged bases, nucleotides, or various DNA intermediate structures [3]. Flap endonuclease 1 (FEN1) is a member of the family that promotes DNA replication and repair [4]. As a structure-specific nuclease, FEN1 stimulates Okazaki fragment maturation during DNA repair and its efficient removal of 5’-flaps during longpatch base excision repair [5]. FEN1 is reported to possess the activities of 5’ end exonuclease and gap dependence endonuclease, which can promote apoptosis-induced DNA fragmentation in response to apoptotic stimuli [5, 6]. FEN1 maintains the stability of the genome that supports multiple DNA metabolic pathways
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