|Table of Contents|

PERK signaling pathway mediates 5-fluorouracil resistance in colon cancer cells

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2020 06
Page:
897-901
Research Field:
Publishing date:

Info

Title:
PERK signaling pathway mediates 5-fluorouracil resistance in colon cancer cells
Author(s):
Rukeya·Maimaiti; He Xiaolei; Guo Qin
Department of Gastroenterology,Thoracic Hospital of Xinjiang Uygur Autonomous Region,Xinjiang Urumqi 830000,China.
Keywords:
PERK; 5-FU; chemotherapeutic resistance; eIF2alpha; ATF4; CHOP; XIAP
PACS:
R735.35
DOI:
10.3969/j.issn.1672-4992.2020.06.006
Abstract:
Objective：To observe the effect of PERK protein on the chemotherapeutic resistance of colon cancer cells and to further explore its related mechanism.Methods:Colon cancer cell line HCT116 was divided into three groups:Blank control group（Control),down-regulation of PERK expression（si-PERK) group and negative control group（si-NC).Immunofluorescence and RT-PCR were used to verify the transfection efficiency.CCK-8 assay was used to detect the sensitivity of colon cancer cells to 5-FU after down-regulation of PERK expression.Annexin V-FITC apoptosis test was used to detect the effect of down-regulation of PERK expression on apoptosis of colon cancer cells.RT-PCR and Western Blot were used to detect the changes of the expression of key molecules eIF2alpha,ATF4,CHOP and XIAP in PERK signaling pathway.Results:RT-PCR assay showed that compared with the control group,the expression of mRNA in the si-PERK group decreased significantly（P＜0.05),and the transfection efficiency of immunofluorescence was more than 80%.CCK-8 assay showed that compared with the si-NC group,the half inhibitory concentration（IC50) of 5-FU on the cells of si-PERK group was significantly lower（P＜0.01).Annexin V-FITC apoptotic experiment showed that compared with the si-NC group,the apoptotic rate of cells in the si-PERK group was significantly higher（P＜0.05).RT-PCR and Western Blot experiments showed that compared with the si-NC group,the expressions of eIF2alpha,ATF4 and CHOP,the downstream key molecules of PERK signaling pathway,were significantly lower in the si-PERK group（P＜0.05).Conclusion:After inhibiting the expression of PERK in colon cancer cells,it may promote cell apoptosis by down-regulating the expression of eIF2alpha,ATF4 and CHOP,thus promoting cell sensitivity to 5-FU.

References:

[1] Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015［J］.CA:A Cancer Journal for Clinicians,2016,66(2):115-132.
[2] YAO TT,HAO JQ.The clinical characteristics and survival analysis in 398 patients with left or right-sided colon cancer［J］.Modern Oncology,2018,26(13):2068-2072.［姚婷婷,郝吉庆.398例左、右半结肠癌患者的临床特点及生存分析［J］.现代肿瘤医学,2018,26(13):2068-2072.］
[3] Saint-Martin A,Martinez-Rios J,Castaneda-Patlan MC,et al.Functional interaction of hypoxia-inducible factor 2-alpha and autophagy mediates drug resistance in colon cancer cells［J］.Cancers（Basel),2019,11(6):755.
[4] WEN YF,WANG J,BI JW.The relationship of PI3K/AKT pathway with 5-fluorouracil drug-resistance in colon cancer cells［J］.Chinese Journal of Cancer Biotherapy,2015,22(6):815-818.［温彦斐，王俊，毕经旺.PI3K/AKT信号通路与结肠癌细胞5-氟尿嘧啶耐药机制的关系［J］.中国肿瘤生物治疗杂志,2015,22(6):815-818.］
[5] Vanacker H,Vetters J,Moudombi L,et al.Emerging role of the unfolded protein response in tumor immunosurveillance［J］.Trends Cancer,2017,3(7):491-505.
[6] Amodio G,Moltedo O,Fasano D,et al.PERK-mediated unfolded protein response activation and oxidative stress in PARK20 fibroblasts［J］.Front Neurosci,2019(13):673.
[7] OUYANG ZR,CHAI S,ZHAO HQ,et al.Research progress of endoplasmic reticulum stress PERK pathway in tumors［J］.Prac Oncol J,2018,32(1):38-41.［欧阳仲瑞，柴双，赵海杞，等.内质网应激PERK通路在肿瘤中的研究进展［J］.实用肿瘤学杂志,2018,32(1):38-41.］
[8] Timalsina S,Arimoto-Matsuzaki K,Kitamura M,et al.Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells［J］.J Biochem,2018,164(5):381-391.
[9] Madden E,Logue SE,Healy SJ,et al.The role of the unfolded protein response in cancer progression:From oncogenesis to chemoresistance［J］.Biol Cell,2019,111(1):1-17.
[10] Vasaikar S,Huang C,Wang X,et al.Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities［J］.Cell,2019,177(4):1035-1049.
[11] Paschke S,Hebart H,Goeb R,et al.Adjuvant chemotherapy of locally advanced colon cancer:Final results of a randomized trial comparing 5-fluorouracil and folinic acid with folfiri［J］.Visc Med,2019,35(2):124-132.
[12] Balsa E,Soustek MS,Thomas A,et al.ER and nutrient stress promote assembly of respiratory chain supercomplexes through the PERK-eIF2alpha axis［J］.Mol Cell,2019,74(5):877-890.
[13] Chen Y,Zhang B,Cao S,et al.Gandouling combined with Penicillamine improves cerebrovascular injury via PERK/eIF2alpha/CHOP endoplasmic reticulum stress pathway in the mouse model of Wilson's disease［J］.Biosci Rep,2018,38(5):BSR20180800.
[14] Ma J,Yang YR,Chen W,et al.Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells［J］.Oncol Rep,2016,36(2):676-684.
[15] Fang D,Wang H,Li M,et al.Alpha-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3［J］.Biosci Rep,2019,39(6):BSR20190696.
[16] Leung D,Nguyen T,Oliver EM,et al.Combined PPARgamma activation and XIAP inhibition as a potential therapeutic strategy for ovarian granulosa cell tumors［J］.Mol Cancer Ther,2019,18(2):364-375.
[17] Zhang Y,Huang F,Luo Q,et al.Inhibition of XIAP increases carboplatin sensitivity in ovarian cancer［J］.Onco Targets Ther,2018(11):8751-8759.
[18] Gao X,Zhang L,Wei Y,et al.Prognostic value of XIAP level in patients with various cancers:A systematic review and Meta-analysis［J］.J Cancer,2019,10(6):1528-1537.
[19] Flanagan L,Kehoe J,Fay J,et al.High levels of X-linked inhibitor-of-apoptosis protein（XIAP) are indicative of radio chemotherapy resistance in rectal cancer［J］.Radiat Oncol,2015(10):131.

Memo

Memo:
新疆维吾尔自治区卫生健康青年医学科技人才专项科研项目（编号：WJWY-201946）
Last Update: 2020-01-21