核受体FXR激活对宫颈癌CaSki细胞增殖的抑制效应及其作用机制

doi:10.3969/j.issn.1004-616x.2021.04.011

癌变·畸变·突变 ›› 2021, Vol. 33 ›› Issue (4): 302-306.doi: 10.3969/j.issn.1004-616x.2021.04.011

核受体FXR激活对宫颈癌CaSki细胞增殖的抑制效应及其作用机制

黄晓华¹, 牛永东², 石刚刚²

1. 汕头大学医学院第二附属医院, 广东汕头 515041;
2. 汕头大学医学院, 广东汕头 515041

收稿日期:2020-05-30 修回日期:2020-09-07 出版日期:2021-07-30 发布日期:2021-07-29
通讯作者: 石刚刚,E-mail:ggshi@stu.edu.cn E-mail:ggshi@stu.edu.cn
作者简介:黄晓华,E-mail:xhhuang2@foxmail.com。
基金资助:
广东省医学科学技术研究基金（2015120104622949）

Inhibitory effects and mechanisms of nuclear receptor FXR activation in cervical cancer cell line CaSki

HUANG Xiaohua¹, NIU Yongdong², SHI Ganggang²

1. The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041;
2. Shantou University Medical College, Shantou 515041, Guangdong, China

Received:2020-05-30 Revised:2020-09-07 Online:2021-07-30 Published:2021-07-29

摘要/Abstract

摘要： 目的：探讨激活法尼醇X受体（FXR）对宫颈癌CaSki细胞增殖的抑制效应及其作用机制。方法：用10 μmol/L FXR激动剂GW4064处理CaSki细胞，同时以DMSO处理组细胞为对照。分别于处理24和48 h后，采用荧光定量PCR和Western blot检测CaSki细胞FXR mRNA和蛋白的表达情况，用四甲基噻唑蓝（MTT）法检测激活FXR后CaSki细胞的增殖率，流式细胞技术检测细胞凋亡率，Western blot检测p53蛋白的表达水平。结果：与对照组相比，GW4064作用组CaSki细胞FXR mRNA和蛋白的表达水平升高，细胞增殖率降低，细胞凋亡率升高，同时p53蛋白的表达水平升高（均为P<0.05）。结论：激活FXR可抑制CaSki细胞株增殖并促进细胞凋亡，这可能与上调p53表达有关。

关键词: 法尼醇X受体, CaSki细胞, 细胞增殖, 凋亡, p53

Abstract: OBJECTIVE: To investigate inhibitory effects and the mechanisms of farnesoid X receptor (FXR) on proliferation of a cervical cancer cell line,CaSki. METHODS: FXR was activated by the FXR agonist GW4064 and DMSO was set as the control group at the same time. After treatment with 10 μmol/L GW4064 for 24 and 48 h,the mRNA and protein levels of FXR were detected by fluorescence quantitative PCR and Western blot,respectively. Proliferations of CaSki were detected by using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay after FXR activation. Cell apoptosis of CaSki was detected by flow cytometry. Western blot was used to detect protein levels of p53. RESULTS: Compared with the control group,expression levels of FXR mRNA and protein in the GW4064 treatment group were increased,cell proliferation rates were decreased,apoptosis rates were increased,and expression levels of p53 protein were increased (all P<0.05). CONCLUSION: Activation of FXR inhibited proliferation of CaSki through promoting cell apoptosis which might be related to increased expression of p53.

Key words: farnesoid X receptor, CaSki, cell proliferation, apoptosis, p53

中图分类号:

R737.33

黄晓华, 牛永东, 石刚刚. 核受体FXR激活对宫颈癌CaSki细胞增殖的抑制效应及其作用机制[J]. 癌变·畸变·突变, 2021, 33(4): 302-306.

HUANG Xiaohua, NIU Yongdong, SHI Ganggang. Inhibitory effects and mechanisms of nuclear receptor FXR activation in cervical cancer cell line CaSki[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(4): 302-306.

参考文献

[1] JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics[J]. CA:A Cancer J Clin, 2011, 61(2):69-90.
[2] DU P L, WU K S, FANG J Y, et al. Cervical cancer mortality trends in China, 1991-2013, and predictions for the future[J]. Asian Pac J Cancer Prev, 2015, 16(15):6391-6396.
[3] YANG X, LU L. Expression of HPV-16 E6 protein and p53 inactivation increases the uterine cervical cancer invasion[J]. Drug Res (Stuttg), 2015, 65(2):70-73.
[4] DESHPANDE R, MANSARA P, KAUL-GHANEKAR R. Alpha-linolenic acid regulates Cox2/VEGF/MAP kinase pathway and decreases the expression of HPV oncoproteins E6/E7 through restoration of p53 and Rb expression in human cervical cancer cell lines[J]. Tumour Biol, 2016, 37(3):3295-3305.
[5] SEOL W, CHOI H S, MOORE D D. Isolation of proteins that interact specifically with the retinoid X receptor:two novel orphan receptors[J]. Mol Endocrinol, 1995, 9(1):72-85.
[6] FORMAN B M, GOODE E, CHEN J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites[J]. Cell, 1995, 81(5):687-693.
[7] DING L, YANG L, WANG Z, et al. Bile acid nuclear receptor FXR and digestive system diseases[J]. Acta Pharm Sin B, 2015, 5(2):135-144.
[8] ZHU J B, XU S, LI J, et al. Farnesoid X receptor agonist obeticholic acid inhibits renal inflammation and oxidative stress during lipopolysaccharide-induced acute kidney injury[J]. Eur J Pharmacol, 2018, 838:60-68.
[9] HUANG H, XU Y, ZHU J, et al. Recent advances in non-steroidal FXR antagonists development for therapeutic applications[J]. Curr Top Med Chem, 2014, 14(19):2175-2187.
[10] ANAYA-HERNáNDEZ A, MéNDEZ-TEPEPA M, HERNáNDEZ-ARAGóN L G, et al. Farnesoid X receptor immunolocalization in reproductive tissues of adult female rabbits[J]. Acta Histochem, 2014, 116(6):1068-1074.
[11] LI X L, WANG Z M, KLAUNIG J E. Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease[J]. Toxicology, 2018, 410:199-213.
[12] YE L S, JIANG Y, ZUO X X. Farnesoid-X-receptor expression in monocrotaline-induced pulmonary arterial hypertension and right heart failure[J]. Biochem Biophys Res Commun, 2015, 467(1):164-170.
[13] XU X, XU X, LIU P, et al. Structural basis for small molecule NDB (N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2, 6-dichloro-4-(dimethylamino) benzamide) as a selective antagonist of farnesoid X receptor α (FXRα) in stabilizing the homodimerization of the receptor[J]. J Biol Chem, 2015, 290(32):19888-19899.
[14] LIU X J, ZHANG X W, JI L L, et al. Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma[J]. Oncotarget, 2015, 6(6):4226-4238.
[15] HUANG X F, ZHAO W Y, HUANG W D. FXR and liver carcinogenesis[J]. Acta Pharmacol Sin, 2015, 36(1):37-43.
[16] GIAGINIS C, KOUTSOUNAS I, ALEXANDROU P, et al. Elevated Farnesoid X Receptor (FXR) and Retinoid X Receptors (RXRs) expression is associated with less tumor aggressiveness and favourable prognosis in patients with pancreatic adenocarcinoma[J]. Neoplasma, 2015, 62(2):332-341.
[17] DUAN J H, FANG L. microRNA-92 promotes gastric cancer cell proliferation and invasion through targeting FXR[J]. Tumour Biol, 2014, 35(11):11013-11019.
[18] DAI J Q, WANG H X, SHI Y H, et al. Impact of bile acids on the growth of human cholangiocarcinoma via FXR[J]. J Hematol Oncol, 2011, 4:41.
[19] NIU Y D, WANG Z L, HUANG H H, et al. Activated pregnane X receptor inhibits cervical cancer cell proliferation and tumorigenicity by inducing G2/M cell-cycle arrest[J]. Cancer Lett, 2014, 347(1):88-97.
[20] JUŘICA J, DOVRTěLOVá G, NOSKOVá K, et al. Bile acids, nuclear receptors and cytochrome P450[J]. Physiol Res, 2016, 65(Sup 4):S427-S440.
[21] JUNG D, MANGELSDORF D J, MEYER U A. Pregnane X receptor is a target of farnesoid X receptor[J]. J Biol Chem, 2006, 281(28):19081-19091.
[22] ALASMAEL N, MOHAN R, MEIRA L B, et al. Activation of the farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential[J]. Cancer Lett, 2016, 370(2):250-259.
[23] CATALANO S, PANZA S, MALIVINDI R, et al. Inhibition of leydig tumor growth by farnesoid X receptor activation:The in vitro and in vivo basis for a novel therapeutic strategy[J]. Int J Cancer, 2013, 132(10):2237-2247.
[24] BARRASA J I, SANTIAGO-GóMEZ A, OLMO N, et al. Resistance to butyrate impairs bile acid-induced apoptosis in human colon adenocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax[J]. Biochim Biophys Acta, 2012, 1823(12):2201-2209.
[25] IM E O, CHOI Y H, PAIK K J, et al. Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells[J]. Cancer Lett, 2001, 163(1):83-93.
[26] AUBREY B J, KELLY G L, JANIC A, et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?[J]. Cell Death Differ, 2018, 25(1):104-113.
[27] INGARAMO M C, SáNCHEZ J A, DEKANTY A. Regulation and function of p53:a perspective from Drosophila studies[J]. Mech Dev, 2018, 154:82-90.
[28] GUHA G, LU W L, LI S, et al. Novel pactamycin analogs induce p53 dependent cell-cycle arrest at S-phase in human head and neck squamous cell carcinoma (HNSCC) cells[J]. PLoS One, 2015, 10(5):e0125322.
[29] YADAV V, SULTANA S, YADAV J, et al. Gatifloxacin induces S and G2-phase cell cycle arrest in pancreatic cancer cells via p21/p27/p53[J]. PLoS One, 2012, 7(10):e47796.
[30] JANIC A, VALENTE L J, WAKEFIELD M J, et al. DNA repair processes are critical mediators of p53-dependent tumor suppression[J]. Nat Med, 2018, 24(7):947-953.
[31] KONG B, ZHU Y, LI G D, et al. Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 310(5):G295-G302.

核受体FXR激活对宫颈癌CaSki细胞增殖的抑制效应及其作用机制

Inhibitory effects and mechanisms of nuclear receptor FXR activation in cervical cancer cell line CaSki

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