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Curcumin increases breast cancer cell sensitivity to cisplatin by decreasing FEN1 expression.

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.

SUBMITTER: Zou J

PROVIDER: S-EPMC5834274 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Curcumin increases breast cancer cell sensitivity to cisplatin by decreasing FEN1 expression.

Zou Jiao J Zhu Linlin L Jiang Xiaomei X Wang Yang Y Wang Yue Y Wang Xiangwei X Chen Bin B

Oncotarget 20180110 13

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 cispla ...[more]

PMID: 29541412

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Project description:BackgroundDrug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers.MethodsTo reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients.ResultsWe observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.ConclusionAltogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.

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Curcumin increases breast cancer cell sensitivity to cisplatin by decreasing FEN1 expression.

Publications

Curcumin increases breast cancer cell sensitivity to cisplatin by decreasing FEN1 expression.

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