雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER<sup>+</sup>乳腺癌的作用

袁烈; 周维英; 周端方; 刘旭; 李小丽

doi:10.16016/j.2097-0927.202304042

您当前的位置：

首页 >

文章列表页 >

雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER⁺乳腺癌的作用

基础医学 | 更新时间：2026-01-09

- 雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER⁺乳腺癌的作用
- anti-ER⁺ breast cancer by activating endoplasmic reticulum stress to induce apoptosis
- 陆军军医大学学报 2023年45卷第19期页码：2065-2073
- 作者机构：
  
  1.400016 重庆，重庆医科大学：药学院药理学系
  2.400016 重庆，重庆医科大学：药物代谢研究重庆市重点实验室
  3.610031 成都，成都市第三人民医院药学部
- 作者简介：
  
  [ 李小丽, E-mail:lixiaoli@cqmu.edu.cn LI Xiaoli, E-mail:lixiaoli@cqmu.edu.cn
- 基金信息：
  
  重庆市自然科学基金面上项目(cstc2020jcyjmsxmX0223);重庆市研究生科研创新项目(CYS22371)
- DOI：10.16016/j.2097-0927.202304042
  中图分类号： R285.5;R730.53;R737.9
- 收稿：2023-04-11，
  
  修回：2023-06-01，
  
  纸质出版：2023-10-15
- 稿件说明：
移动端阅览
袁烈, 周维英, 周端方, 等. 雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER⁺乳腺癌的作用[J]. 陆军军医大学学报, 2023,45(19):2065-2073.

Lie YUAN, Weiying ZHOU, Duanfang ZHOU, et al. anti-ER⁺ breast cancer by activating endoplasmic reticulum stress to induce apoptosis[J]. Journal of Army Medical University, 2023, 45(19): 2065-2073.
袁烈, 周维英, 周端方, 等. 雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER⁺乳腺癌的作用[J]. 陆军军医大学学报, 2023,45(19):2065-2073. DOI： 10.16016/j.2097-0927.202304042.

Lie YUAN, Weiying ZHOU, Duanfang ZHOU, et al. anti-ER⁺ breast cancer by activating endoplasmic reticulum stress to induce apoptosis[J]. Journal of Army Medical University, 2023, 45(19): 2065-2073. DOI： 10.16016/j.2097-0927.202304042.

摘要

目的

探讨雷公藤红素(celastrol

Cel)通过激活内质网应激介导的细胞凋亡发挥抗雌激素受体阳性(estrogen receptor positive

)乳腺癌的作用机制。

方法

以ER

人乳腺癌细胞系MCF-7与T47D为研究对象，采用MTT与细胞克隆实验检测Cel对细胞活力与增殖的影响；采用Western blot检测Cel对凋亡相关蛋白表达的影响；分别采用RT-qPCR和Western blot检测Cel对内质网应激相关基因和蛋白表达的影响；体内建立MCF-7细胞裸鼠原位移植瘤模型，观察Cel对移植瘤生长的影响。

结果

MTT与细胞克隆实验结果显示，Cel可呈

剂量依赖性抑制MCF-7与T47D细胞活力与增殖(

＜0.05)；Western blot结果显示，Cel可上调凋亡相关蛋白Cleaved PARP与BAX表达，并下调BCL-2表达(

＜0.05)；RT-qPCR结果显示，Cel可上调内质网应激相关基因IRE1α、ATF6、PERK、ATF4、CHOP、BIP的表达水平(

＜0.05)；Cel可诱导内质网应激标志蛋白BIP表达升高，PERK通路相关蛋白p-PERK、p-eIF2α、ATF4、CHOP表达增加，IRE1α通路相关蛋白p-IRE1α、XBP1s表达增加，ATF6通路中的Cleaved ATF6水平增加；体内实验结果显示，Cel能显著降低裸鼠原位移植瘤的体积(

＜0.05)，且对裸鼠体质量无明显的影响。

结论

Cel具有一定的抑制ER

乳腺癌MCF-7及T47D细胞增殖的作用，其机制可能与激活内质网应激信号通路从而诱导细胞凋亡有关。

Abstract

Objective

To investigate the mechanism of celastrol (Cel) against estrogen receptor positive (ER

) breast cancer by activating endoplasmic reticulum stress-mediated apoptosis.

Methods

human breast cancer cell lines MCF-7 and T47D were used as research objects. MTT assay was used to detect the effect of Cel on cell viability. Western blotting were employed to detect the expression of apoptosis-related proteins. RT-qPCR and Western blotting were applied to measure the expression of endoplasmic reticulum stress-related molecules at mRNA and protein levels. A nude mouse model of orthotopic transplantation of MCF-7 cells was established to observe the effect of Cel on the growth of transplanted tumors.

Results

MTT Results showed that Cel inhibited the viability of MCF-7 and T47D cells in a dose-dependent manner (

0.05). Western blotting showed that Cel up-regulated the expression of apoptosis-related proteins

Cleaved PARP and BAX

and down-regulated the expression of BCL-2 (

0.05). RT-qPCR indicated that Cel up-regulated the mRNA levels of endoplasmic reticulum stress-related genes IRE1α

ATF6

PERK

ATF4

CHOP and BIP (

0.05). Western blotting revealed that Cel treatment resulted in increased expression levels of endoplasmic reticulum stress marker B

of PERK pathway related proteins p-PERK

p-eIF2α

ATF4 and CHOP

of IRE1α pathway associated proteins p-IRE1α and XBP1s

and of ATF6 pathway associated protein Cleared ATF6.

In vivo

experiment Results showed that Cel significantly reduced the volume of orthotopic transplanted tumor in nude mice (

0.05)

and had no significant effect on their body weight.

Conclusion

Cel has a certain inhibitory effect on the proliferation of ER

breast cancer MCF-7 and T47D cells

and its mechanism may be related to the activation of endoplasmic reticulum stress signaling pathway to induce apoptosis.

关键词

Keywords

references

TACCONELLI E, CARRARA E, SAVOLDI A, et al . Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis[J ] . Lancet Infect Dis, 2018, 18(3): 318-327. DOI: 10.1016/S1473-3099(17)30753-3.

MSHEIK Z S, NASSAR F J, CHAMANDI G, et al . MiR-126 decreases proliferation and mammosphere formationof MCF-7 and predicts prognosis of ER+ breast cancer[J ] . Diagnostics (Basel), 2022, 12(3): 745. DOI: 10.3390/diagnostics12030745.

MICHMERHUIZEN A R, LERNER L M, PESCH A M, et al . Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models[J ] . NPJ Breast Cancer, 2022, 8(1): 31. DOI: 10.1038/s41523-022-00397-y.

TSOI H, YOU C P, LEUNG M H, et al . Targeting ribosome biogenesis to combat tamoxifen resistance in ER+ve breast cancer[J ] . Cancers (Basel), 2022, 14(5): 1251. DOI: 10.3390/cancers14051251.

ZHANG Y J, HUANG S, YANG G, et al . The role of miRNAs during endoplasmic reticulum stress induced apoptosis in digestive cancer[J ] . J Cancer, 2021, 12(22): 6787-6795. DOI: 10.7150/jca.62352.

WANG M, KAUFMAN R J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease[J]. Nature, 2016, 529(7586): 326-335. DOI: 10.1038/nature17041.

CAO S L, TANG J Y, HUANG Y C, et al . The road of solid tumor survival: from drug-induced endoplasmic reticulum stress to drug resistance[J ] . Front Mol Biosci, 2021, 8: 620514. DOI: 10.3389/fmolb.2021.620514.

MARROCCO V, TRAN T, ZHU S Y, et al . A small molecule UPR modulator for diabetes identified by high throughput screening[J ] . Acta Pharm Sin B, 2021, 11(12): 3983-3993. DOI: 10.1016/j.apsb.2021.05.018.

MARCINIAK S J. Endoplasmic reticulum stress: a key player in human disease[J]. FEBS J, 2019, 286(2): 228-231. DOI: 10.1111/febs.14740.

WANG F Q, YAO S L, XIA H F. SIRT1 is a key regulatory target for the treatment of the endoplasmic reticulum stress-related organ damage[J]. Biomed Pharmacother, 2020, 130: 110601. DOI: 10.1016/j.biopha.2020.110601.

OU G X, JIANG X Y, GAO A, et al . Celastrol inhibits canine mammary tumor cells by inducing apoptosis via the caspase pathway[J ] . Front Vet Sci, 2021, 8: 801407. DOI: 10.3389/fvets.2021.801407..

KANNAIYAN R, SHANMUGAM M K, SETHI G. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer[J]. Cancer Lett, 2011, 303(1): 9-20. DOI: 10.1016/j.canlet.2010.10.025.

LI X L, ZHU G B, YAO X T, et al . Celastrol induces ubiquitin-dependent degradation of mTOR in breast cancer cells[J ] . OncoTargets Ther, 2018, 11: 8977-8985. DOI: 10.2147/OTT.S187315.

GAO W L, NIU L, CHEN W L, et al . Integrative analysis of the expression levels and prognostic values for NEK family members in breast cance r[J ] . Front Genet, 2022, 13: 798170. DOI: 10.3389/fgene.2022.798170.

ODLE T G. Precision medicine in breast cancer[J]. Radiol Technol, 2017, 88(4): 401M-421M.

REN B, LIU H, GAO H, et al . Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR[J ] . Oncotarget, 2017, 8(54): 93039-93050. DOI: 10.18632/oncotarget.21750..

LUNA-MARCO C, UBINK A, KOPSIDA M, et al . Endoplasmic reticulum stress and metabolism in hepatocellular carcinoma[J ] . Am J Pathol, 2022: S0002-S9440(22)00322-4. DOI: 10.1016/j.ajpath.2022.09.012.

DE LA CALLE C M, SHEE K, YANG H, et al . The endoplasmic reticulum stress response in prostate cancer[J ] . Nat Rev Urol, 2022, 19(12): 708-726. DOI: 10.1038/s41585-022-00649-3.

SALVAGNO C, MANDULA J K, RODRIGUEZ P C, et al . Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity[J ] . Trends Cancer, 2022, 8(11): 930-943. DOI: 10.1016/j.trecan.2022.06.006.

JIANG W X, CHEN L, GUO X, et al . Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy[J ] . Theranostics, 2022, 12(6): 2987-3006. DOI: 10.7150/thno.71693.

ZHANG Y M, LIAO S C, FAN W, et al . Tunicamycin-induced ER stress regulates chemokine CCL5 expression and secretion via STAT3 followed by decreased transmigration of MCF-7 breast cancer cells[J ] . Oncol Rep, 2014, 32(6): 2769-2776. DOI: 10.3892/or.2014.3479..

CHOI Y K, KANG J I, HAN S, et al . L-ascorbic acid inhibits breast cancer growth by inducing IRE/JNK/CHOP-related endoplasmic reticulum stress-mediated p62/SQSTM1 accumulation in the nucleus[J ] . Nutrients, 2020, 12(5): 1351. DOI: 10.3390/nu12051351.

MARCINIAK S J, YUN C Y, OYADOMARI S, et al . CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum[J ] . Genes Dev, 2004, 18(24): 3066-3077. DOI: 10.1101/gad.1250704.

CONNOR J H, WEISER D C, LI S, et al . Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inh ibitor 1[J ] . Mol Cell Biol, 2001, 21(20): 6841-6850. DOI: 10.1128/MCB.21.20.6841-6850.2001.

CULLINAN S B, ZHANG D, HANNINK M, et al . Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival[J ] . Mol Cell Biol, 2003, 23(20): 7198-7209. DOI: 10.1128/MCB.23.20.7198-7209.2003.

OAKES S A. Endoplasmic reticulum stress signaling in cancer cells[J]. Am J Pathol, 2020, 190(5): 934-946. DOI:10.1016/j.ajpath.2020.01.010.

YE J, RAWSON R B, KOMURO R, et al . ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs[J ] . Mol Cell, 2000, 6(6): 1355-1364. DOI: 10.1016/s1097-2765(00)00133-7.

MORISHIMA N, NAKANISHI K, NAKANO A. Activating transcription factor-6 (ATF6) mediates apoptosis with reduction of myeloid cell leukemia sequence 1 (Mcl-1) protein via induction of WW domain binding protein 1[J ] . J Biol Chem, 2011, 286(40): 35227-35235. DOI: 10.1074/jbc.M111.233502.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

Gm49394对胰岛β细胞凋亡的调控及机制研究

下调钙网蛋白基因表达可促进肝星状细胞凋亡

对氧磷酶2对氧化低密度脂蛋白诱导的乳鼠心肌细胞损伤的影响

光敏剂MPPa介导光动力诱导人乳腺癌细胞MCF-7的内质网应激途径凋亡

内质网应激在软脂酸钠诱导的脂肪变性L02肝细胞凋亡中的作用

雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER+乳腺癌的作用

anti-ER+ breast cancer by activating endoplasmic reticulum stress to induce apoptosis

DOI：10.16016/j.2097-0927.202304042

摘要

Abstract

关键词

Keywords

references

雷公藤红素通过激活内质网应激介导的细胞凋亡发挥抗ER⁺乳腺癌的作用

anti-ER⁺ breast cancer by activating endoplasmic reticulum stress to induce apoptosis