Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel <italic style="font-style: italic">via</italic> activation of JNK/mitochondrial pathway

Yue LEI; Jie WAN; Dandan LI; Lin YE; Yanan LIU; Lin ZHU; Hongyan CHEN

doi:10.16016/j.1000-5404.201711248

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Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel via activation of JNK/mitochondrial pathway

Basic Medicine | 更新时间：2026-01-09

- Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel via activation of JNK/mitochondrial pathway
- Journal of Third Military Medical University Vol. 40, Issue 9, Pages: 780-787(2018)
- 作者机构：
  
  1.400016 重庆, 重庆医科大学附属第一医院:耳鼻喉头颈外科
  2.400016 重庆, 重庆医科大学附属第一医院:胸心外科
  3.332000 江西九江, 江西省九江市第一人民医院耳鼻喉头颈外科
  4.646000 四川泸州, 西南医科大学附属医院耳鼻咽喉-头颈外科
- 作者简介：
- 基金信息：
  
  the Project of Science and Technology Plan of Yuzhong District, Chongqing(20120203)
- DOI：10.16016/j.1000-5404.201711248
  CLC： R73-362;R739.63;R979.19
- Received：29 November 2017，
  
  Revised：2018-01-29，
  
  Published：15 May 2018
- 稿件说明：
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Yue LEI, Jie WAN, Dandan LI, et al. Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel via activation of JNK/mitochondrial pathway[J]. Journal of Third Military Medical University, 2018, 40(9): 780-787.
DOI：

Yue LEI, Jie WAN, Dandan LI, et al. Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel via activation of JNK/mitochondrial pathway[J]. Journal of Third Military Medical University, 2018, 40(9): 780-787. DOI： 10.16016/j.1000-5404.201711248.

摘要

目的

探讨特异性小干扰RNA(small interfering RNA

siRNA)沉默转录因子叉头框M1(FoxM1)对人鼻咽癌HONE-1细胞增殖、凋亡、紫杉醇敏感性的影响及可能的分子机制。

方法

采用siRNA靶向沉默鼻咽癌HONE-1细胞FoxM1表达并通过RT-PCR、实时定量PCR、Western blot检测转染后FoxM1的表达水平。siRNA转染后细胞的增殖和对紫杉醇的敏感性采用MTT法检测

流式细胞仪检测细胞周期分布

Annexin V-FITC/PI双染法检测细胞凋亡率。Western blot检测Ki67、CyclinE1、多药耐药基因1(multidrug resistance 1

MDR1)及c-Jun氨基末端激酶(c-Jun N-terminal kinase

JNK)、p-JNK、c-Jun、p-c-Jun、凋亡相关蛋白Bax、Bcl-2的表达水平。

结果

转染后FoxM1 mRNA及蛋白的表达均被下调(

0.01)。siRNA转染组细胞增殖速率减缓(

0.05)

Ki67表达降低(

0.05)。siRNA转染组G

期细胞比例增加(

0.01)

S期比例减低(

0.05)

Cyclin E1低表达(

0.01)。同时

siRNA+紫杉醇组凋亡率明显高于阴性及空白对照+紫杉醇组(

0.01)。siRNA转染组细胞MDR1水平下降(

0.05)

对紫杉醇的敏感性较两对照组明显增强(

0.01)。siRNA+紫杉醇组与阴性对照+紫杉醇组相比p-JNK1、p-c-Jun、Bax表达上调(

0.01)

Bcl-2表达下调(

0.01)。

结论

特异性siRNA沉默FoxM1表达可以影响JNK/线粒体通路活性

抑制鼻咽癌HONE-1细胞增殖

促进其凋亡

提高其对紫杉醇的敏感性。

Abstract

Objective

To determine the effects of down-regulating Forkhead box M1 gene (FoxM1) on the proliferation

apoptosis and sensitivity to paclitaxel in human nasopharyngeal carcinoma cell line HONE-1

and investigate the possible molecular mechanism.

Methods

A sequence-specific small interfering RNA (siRNA) targeting FoxM1 was used to transfect HONE-1 cells

then the expression of FoxM1 was detected by quantitative reverse transcription-PCR (qRT-PCR)

RT-PCR and Western blotting.The proliferation and chemosensitivity to paclitaxel cells were detected by MTT assay.Flow cytometry was adopted to measure the cell cycle distribution of transfected HONE-1 cells.The apoptotic rates were examined by Annexin V-FITC/PI staining assay.And the expression levels of Ki67

Cyclin E1

multidrug resistance 1 (MDR1)

c-Jun N-terminal kinase (JNK)

p-JNK

c-Jun

p-c-Jun

and apoptosis-related proteins Bax and Bcl-2 were detected by Western blotting.

Results

FoxM1-siRNA transfection decreased the expression level of FoxM1 gene in HONE-1 cells obviously (

0.01).Compared with the control cells

the transfected HONE-1 cells had markedly decreased proliferation rate (

0.05)

much lower Ki67 expression (

0.05)

increased percentage of the cells in G

phase (

0.01) while less cells in S phase (

0.05)

and down-regulated expression of Cyclin E1 (

0.01).Meanwhile the apoptotic rate was significantly higher in the siRNA/paclitaxel cells than negative and blank control/paclitaxel cells (

0.01).What's more

the transfection obviously decreased the MDR1 level (

0.05)

and significantly enhanced the sensitivity of HONE-1 cells to paclitaxel (

0.01)

when compared with the control groups.In siRNA/paclitaxel group

the expression levels of p-JNK1

p-c-Jun and Bax were much higher than the negative control/paclitaxel group (all

0.01)

whereas that of Bcl-2 was down-regulated (

0.01).

Conclusion

The siRNA targeting FoxM1 in HONE-1 cells could effectively regulate the activity of JNK/mitochondrial pathway

inhibit the proliferation

promote the apoptosis

and ultimately enhance the sensitivity to paclitaxel.

关键词

Keywords

references

SIEGEL R L, MILLER K D, JEMAL A.Cancer statistics, 2017[J].CA Cancer J Clin, 2017, 67(1):7-30.DOI:10.3322/caac.21387.

CHEN W, ZHENG R, BAADE P D, et al .Cancer statistics in China, 2015[J ] .CA Cancer J Clin, 2016, 66(2):115-132.DOI:10.3322/caac.21338.

CHEN C, WANG F H, AN X, et al .Triplet combination with paclitaxel, cisplatin and 5-FU is effective in metastatic and/or recurrent nasopharyngeal carcinoma[J ] .Cancer Chemoth Pharm, 2012, 71(2):371-378.DOI:10.1007/s00280-012-2020-x.

HE X Y, HU C S, YING H M, et al .Paclitaxel with cisplatin in concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma[J ] .Eur Arch Otorhinolaryngol, 2010, 267(5):773-778.DOI:10.1007/s00405-009-1112-7.

SU S F, HAN F, ZHAO C, et al .Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone[J ] .Int J Radiat Oncol Biol Phys, 2012, 82(1):327-333.DOI:10.1016/j.ijrobp.2010.09.011.

KAMRAN S C, RIAZ N, LEE N.Nasopharyngeal carcinoma[J].Surg Oncol Clin N Am, 2015, 24(3):547-561.DOI:10.1016/j.soc.2015.03.008.

FAYETTE J, MONTELLA A, CHABAUD S, et al .Paclitaxel is effective in relapsed head and neck squamous cell carcinoma:A retrospective study of 66 patients at a single institution[J ] .Anticancer drug, 2010, 21(5):553-558.DOI:10.1097/CAD.0b013e3283388e60.

KWOK J M, PECK B, MONTEIRO L J, et al .FOXM1 confers acquired cisplatin resistancein breastcancer cells[J ] .Mol Cancer Res, 2010, 8(1):24-34.DOI:10.1158/1541-7786.MCR-09-0432.

WANG Y, WEN L, ZHAO S H, et al .FoxM1 expression is significantly associated withcisplatin-based chemotherapy resistance and poor prognosis in advanced non-small celllung cancerpatients[J ] .Lung Cancer, 2013, 79(2):173-179.DOI:10.1016/j.lungcan.2012.10.019.

OKADA K, FUJIWARA Y, TAKAHASHI T, et al .Over-expression of forkhead box M1 transcriptionfactor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel ingastric cancer[J ] .Ann Surg Oncol, 2013, 20(3):1035-1043.DOI:10.1245/s10434-012-2680-0.

WANG K, ZHU X, ZHANG K, et al .FoxM1 inhibition enhances chemosensitivity of docetaxel-resistant A549 cells to docetaxel via activation of JNK/mitochondrial pathway[J ] . Acta Biochim Biophys Sin (Shanghai), 2016, 48(9):804-809.DOI:10.1093/abbs/gmw072..

ZHAO F, SIU M K, JIANG L, et al .Overexpression of forkheadbox protein M1 (FOXM1) in ovarian cancer correlates with poor patient survival and contributes to paclitaxel resistance[J ] .PLoS ONE, 2014, 9(11):e113478.DOI:10.1371/journal.pone.0113478.

JIANG L, WANG P, CHEN H.Overexpression of FOXM1 is associated with metastases of nasopharyngeal carcinoma[J].Ups J Med Sci, 2014, 119(4):324-332.DOI:10.3109/03009734.2014.960053.

魏蕾, 江黎珠, 于超, 等.下调FoxM1表达对人喉癌Hep-2细胞顺铂敏感性的影响[J].第三军医大学学报, 2015, 37(16):1603-1608.DOI:10.16016/j.1000-5404.201411182.

WEI L, JIANG L Z, YU C, et al .FoxM1 down-regulation promotes sensitivity of laryngeal carcinoma Hep-2 cells to cisplatin[J ] .J Third Mil Med Univ, 2015, 37(16):1603-1608.DOI:10.16016/j.1000-5404.201411182.

JIANG L, WANG P, CHEN L, et al .Down-regulation of FoxM1 by thiostrepton or small interfering RNA inhibits proliferation, transformation ability and angiogene sis, and induces apoptosis of nasopharyngeal carcinoma cells[J ] .Int J Clin Exp Pathol, 2014, 7(9):5450-5460.

权芳, 张少强, 白艳霞, 等.白藜芦醇对缺氧环境中鼻咽癌细胞株CNE2的化疗增敏作用[J].中西医结合学报, 2009, 7(10):952-957.

QUAN F, ZHANG S Q, BAI Y X, et al .Resveratrol increases sensitivity of CNE2 cells to chemotherapeutic drugs under hypoxia[J ] .J Chin Integr Med, 2009, 7(10):952-957.

KAESTNER K H, KNOCHEL W, MARTINEZ D E.Unified nomenclature for the wingedhelix/forkhead transcription factors[J].Genes Dev, 2000, 14(2):142-146.

WU Q F, LIU C, TAI M H, et al .Knockdown of FoxM1 by siRNA interference decreasescell proliferation, induces cell cycle arrest and inhibits cell invasion in MHCC-97H cells in vitro [J ] .Acta Pharmacol Sin, 2010, 31(3):361-366.DOI:10.1038/aps.2010.4..

YU J, WANG X, LI Y, et al .TanshinoneⅡA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1[J ] .Oncol Rep, 2017, 37(3):1394-1400.DOI:10.3892/OR.2017.5408.

PANAYOTOPOULOU E G, MÜLLER A K, BÖRRIES M, et al .Targeti ng of apoptotic pathwaysby SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells[J ] .Oncotarget, 2017, 8(28):45088-45104.DOI:10.18632/ONCOTARGET.15125.

JIN H, PARK M H, KIM S M.3, 3'-Diindolylmethane potentiates paclitaxel-induced antitumor effects on gastric cancer cells through the Akt/FOXM1 signaling cascade[J].Oncol Rep, 2015, 33(4):2031-2036.DOI:10.3892/or.2015.3758.

HUANG X, QIN J, LU S.Up-regulation of miR-877 induced by paclitaxel inhibitshepatocellular carcinoma cell proliferation though targeting FOXM1[J].IntJ Clin Exp Pathol, 2015, 8(2):1515-1524.

FREDERIKS C N, LAM S W, GUCHELAAR H J, et al .Genetic polymorphisms andpaclitaxel-or docetaxel-induced toxicities:A systematic review[J ] .Cancer Treat Rev, 2015, 41(10):935-950.DOI:10.1016/j.ctrv.2015.10.010.

ZHAO Y, MU X, DU G.Microtubule-stabilizing agents:New drug discovery and cancer therapy[J].Pharmacol Ther, 2016, 162:134-143.DOI:10.1016/j.pharmthera.2015.12.006.

HOU Y, ZHU Q, LI Z, et al .The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cell s[J ] .Cell Death Dis, 2017, 8(3):e2659.DOI:10.1038/cddis.2017.53.

WANG I C, CHEN Y J, HUGHES D E, et al .FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness[J ] .J Biol Chem, 2008, 283(30):20770-20778.DOI:10.1074/jbc.M709892200.

WADA T, PENNINGER J M.Mitogen-activated protein kinases in apoptosisregulation[J].Oncogene, 2004, 23(16):2838-2849.DOI:10.1038/sj.onc.1207556.

RAGGATT L J, EVDOKIOU A, FINDLAY D M.Sustained activation of Erk1/2 MAPK and cell growth suppression by the insert-negative, but not the insert-positive isoform of the human calcitonin receptor[J].J Endocrinol, 2000, 167(1):93-105.

CHATTOPADHYAY S, MACHADO-PINILLA R, MANGUAN-GARCÍA C, et al .MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer[J ] .Oncogene, 2006, 25(23):3335-3345.DOI:10.1038/sj.onc.1209364.

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⁰

Down-regulation of FoxM1 enhances sensitivity of human nasopharyngeal carcinoma cells to paclitaxel via activation of JNK/mitochondrial pathway

DOI：10.16016/j.1000-5404.201711248

摘要

Abstract

关键词

Keywords

references