乳腺癌中线粒体功能障碍与CPT1A/ERK信号转导通路共同调节乳腺癌恶性行为的机制研究

姜丹; 宋国庆; 王晓丹

doi:10.19401/j.cnki.1007-3639.2024.07.004

您当前的位置：

首页 >

文章列表页 >

乳腺癌中线粒体功能障碍与CPT1A/ERK信号转导通路共同调节乳腺癌恶性行为的机制研究

论著 | 更新时间：2025-12-31

- 乳腺癌中线粒体功能障碍与CPT1A/ERK信号转导通路共同调节乳腺癌恶性行为的机制研究
- Study on the mechanism of mitochondrial dysfunction and CPT1A/ERK signal transduction pathway regulating malignant behavior in breast cancer
- 中国癌症杂志 2024年34卷第7期页码：650-658
- 作者机构：
  
  1. 中国医科大学附属盛京医院乳腺肿瘤外科，辽宁沈阳 110000
  2. 中国医科大学附属盛京医院胸外科，辽宁沈阳 110000
- 作者简介：
  
  [ "姜丹（ORCID: 0009-0001-3598-0032），本科。" ]
  宋国庆（ORCID: 0009-0009-7786-672X），硕士，副教授、副主任医师。
- 基金信息：
  
  辽宁省科学技术计划项目(2019-ZD-0780)
- DOI：10.19401/j.cnki.1007-3639.2024.07.004
  中图分类号： R737.9
- 收稿：2023-10-30，
  
  修回：2024-06-15，
  
  纸质出版：2024-07-30
- 稿件说明：
移动端阅览
姜丹, 宋国庆, 王晓丹. 乳腺癌中线粒体功能障碍与CPT1A/ERK信号转导通路共同调节乳腺癌恶性行为的机制研究[J]. 中国癌症杂志, 2024,34(7):650-658.

Dan JIANG, Guoqing SONG, Xiaodan WANG. Study on the mechanism of mitochondrial dysfunction and CPT1A/ERK signal transduction pathway regulating malignant behavior in breast cancer[J]. China Oncology, 2024, 34(7): 650-658.
姜丹, 宋国庆, 王晓丹. 乳腺癌中线粒体功能障碍与CPT1A/ERK信号转导通路共同调节乳腺癌恶性行为的机制研究[J]. 中国癌症杂志, 2024,34(7):650-658. DOI： 10.19401/j.cnki.1007-3639.2024.07.004.

Dan JIANG, Guoqing SONG, Xiaodan WANG. Study on the mechanism of mitochondrial dysfunction and CPT1A/ERK signal transduction pathway regulating malignant behavior in breast cancer[J]. China Oncology, 2024, 34(7): 650-658. DOI： 10.19401/j.cnki.1007-3639.2024.07.004.

摘要

背景与目的：

肉碱棕榈酰转移酶1A（carnitine palmitoyl transferase 1A，CPT1A）的高表达与乳腺癌患者预后较差相关，且能促进线粒体对脂肪酸的利用并最大限度地提高三磷酸腺苷（triphosphate，ATP）产量。然而，CPT1A在乳腺癌转移中的作用仍不清楚。本研究旨在探讨乳腺癌中线粒体功能障碍与CPT1A/细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）信号转导通路共同调节乳腺癌恶性行为的机制。

方法：

分别使用慢病毒系统和shRNA工具在人乳腺癌细胞系MDA-MB-231和MCF7中过表达或敲低CPT1A，将细胞分为NC组、CPT1A组和shCPT1A组。采用transwe

ll实验检测细胞侵袭能力。采用蛋白质印迹法（Western blot）分析细胞中过氧化物酶体增殖物激活受体γ辅激活因子-1α（peroxisome proliferator-activated receptor γ coactivator-1α，PGC-1α）、ERK1/2和CPT1A蛋白的表达。采用线粒体红染色分析MDA-MB-231和MCF7细胞系的线粒体形态，并通过耗氧率分析线粒体呼吸能力。

结果：

与表达对照载体的细胞相比，CPT1A过表达导致MCF7细胞和MDA-MB-231细胞侵袭能力增强（

0.05），shCPT1A敲低导致细胞侵袭能力降低（

0.05）。与NC组相比，CPT1A组MDA-MB-231和MCF7细胞中线粒体分支长度显著变短（

0.05），ERK1/2、PGC-1α表达显著增加（

0.05），shCPT1A组MDA-MB-231和MCF7细胞中线粒体分支长度显著变长（

0.05），ERK1/2、PGC-1α表达显著降低（

0.05）。此外，与NC组相比，CPT1A组MDA-MB-231细胞基础和最大呼吸能力以及ATP产量显著增加（

0.05），而shCPT1A组MDA-MB-231细胞基础和最大呼吸能力以及ATP产量显著降低（

0.05）。

结论：

CPT1A激活的ERK1/2-PGC-1α信号转导通路在线粒体分裂介导的乳腺癌细胞转移中发挥重要作用。

Abstract

Background and purpose:

The overexpression of carnitine palmitoyl transferase 1A (CPT1A) is related to the poor prognosis of breast cancer

and it can promote the utilization of fatty acids by mitochondria and maximize triphosphate (ATP) production. However

the role of CPT1A in breast cancer metastasis is still unclear. This study aimed to explore the mechanism that mitochondrial dysfunction and CPT1A/extracellular signal-regulated kinase (ERK) signaling pathway in breast cancer jointly regulate the malignant behavior of breast cancer.

Methods:

The lentivirus system and shRNA tools were used to overexpress or knock down CPT1A in human breast cancer cell lines MDA-MB-231 and MCF7

and the cells were divided into NC group

CPT1A group and shCPT1A group. The invasion ability of cells was detected by transwell assay

and the protein expressions of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)

ERK1/2 and CPT1A were analyzed by Western blot. The mitochondrial morphology of MDA-MB-231 and MCF7 cell lines was analyzed using mitochondrial red staining

and mitochondrial respiratory capacity was analyzed by oxyge

n consumption rate.

Results:

Compared with cells expressing control vector

overexpression of CPT1A resulted in enhanced invasion abilities of MCF7 cells and MDA-MB-231 cells (

0.05)

while knockdown of shCPT1A resulted in decreased invasion abilities of cells (

0.05). Compared with NC group

the length of mitochondrial branches in MDA-MB-231 and MCF7 cells in CPT1A group was significantly shorter (

0.05)

and the expressions of ERK1/2 and PGC-1α increased significantly (

0.05). In shCPT1A group

the length of mitochondrial branches in MDA-MB-231 and MCF7 cells increased significantly (

0.05)

and the expressions of ERK1/2 and PGC-1α decreased significantly (

0.05). In addition

compared with NC group

the cellular basis

maximum respiratory capacity and ATP production of MDA-MB-231 in CPT1A group increased significantly (

0.05)

while the cellular basis

maximum respiratory capacity and ATP production of MDA-MB-231 in shCPT1A group decreased significantly (

0.05).

Conclusion:

ERK1/2-PGC-1α activated by CPT1A Signaling pathway plays a key role in mitochondrial division mediated breast cancer cell metastasis.

关键词

Keywords

references

GIAQUINTO A N , SUNG H , MILLER K D , et al. Breast cancer statistics, 2022 [J ] . CA Cancer J Clin , 2022 , 72 ( 6 ): 524 - 541 .

XIA C F , DONG X S , LI H , et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants [J ] . Chin Med J , 2022 , 135 ( 5 ): 584 - 590 .

GALIANDRO F , AGNES S , MOSCHETTA G , et al. Prognostic factors in patients with breast cancer liver metastases undergoing liver resection: systematic review and meta-analysis [J ] . Cancers , 2022 , 14 ( 7 ): 1691 .

KOTECHA R , TONSE R , RUBENS M , et al. Systematic review and meta-analysis of breast cancer brain metastasis and primary tumor receptor expression discordance [J ] . Neurooncol Adv , 2021 , 3 ( 1 ): vdab010 .

VONA R , MILEO A M , MATARRESE P . Microtubule-based mitochondrial dynamics as a valuable therapeutic target in cancer [J ] . Cancers , 2021 , 13 ( 22 ): 5812 .

KUMAR H , GUPTA N V , JAIN R , et al. A review of biological targets and therapeutic approaches in the management of triple-negative breast cancer [J ] . J Adv Res , 2023 , 54 : 271 - 292 .

JIANG N , XING B Z , PENG R , et al. Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy [J ] . Mech Ageing Dev , 2022 , 205 : 111688 .

SAVUKAITYTĖ A , BARTNYKAITĖ A , BEKAMPYTĖ J , et al. DDIT4 downregulation by siRNA approach increases the activity of proteins regulating fatty acid metabolism upon aspirin treatment in human breast cancer cells [J ] . Curr Issues Mol Biol , 2023 , 45 ( 6 ): 4665 - 4674 . DOI: 10.3390/cimb45060296 http://doi.org/10.3390/cimb45060296

JOSHI M , KIM J , D’ALESSANDRO A , et al. CPT1A over-expression increases reactive oxygen species in the mitochondria and promotes antioxidant defenses in prostate cancer [J ] . Cancers , 2020 , 12 ( 11 ): 3431 .

DAS M , GIANNOUDIS A , SHARMA V . The role of CPT1A as a biomarker of breast cancer progression: a bioinformatic approach [J ] . Sci Rep , 2022 , 12 ( 1 ): 16441 . DOI: 10.1038/s41598-022-20585-x http://doi.org/10.1038/s41598-022-20585-x

ZHANG W , DU X F , LIU B , et al. Engineering supramolecular nanomedicine for targeted near infrared-triggered mitochondrial dysfunction to potentiate cisplatin for efficient chemophototherapy [J ] . ACS Nano , 2022 , 16 ( 1 ): 1421 - 1435 .

FORTE M , SCHIRONE L , AMERI P , et al. The role of mitochondrial dynamics in cardiovascular diseases [J ] . Br J Pharmacol , 2021 , 178 ( 10 ): 2060 - 2076 .

YOU Y , MURAOKA S , JEDRYCHOWSKI M P , et al. Human neural cell type-specificextracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer’s disease brain [J ] . J Extracell Vesicles , 2022 , 11 ( 1 ): e12183 .

ANSARI M I , BANO N , KAINAT K M , et al. Bisphenol A exposure induces metastatic aggression in low metastatic MCF-7 cells via PGC-1α mediated mitochondrial biogenesis and epithelial-mesenchymal plasticity [J ] . Life Sci , 2022 , 302 : 120649 .

MIDDLETON P , VERGIS N . Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation [J ] . Therap Adv Gastroenterol , 2021 , 14 : 17562848211031394 .

LIU Y E , SHI Y F . Mitochondria as a target in cancer treatment [J ] . MedComm , 2020 , 1 ( 2 ): 129 - 139 . DOI: 10.1002/mco2.16 http://doi.org/10.1002/mco2.16

LEE K M , GILTNANE J M , BALKO J M , et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation [J ] . Cell Metab , 2017 , 26 ( 4 ): 633 - 647 . e7.

PRAHARAJ P P , PATRO B S , BHUTIA S K . Dysregulation of mitophagy and mitochondrial homeostasis in cancer stem cells: novel mechanism for anti-cancer stem cell-targeted cancer therapy [J ] . Br J Pharmacol , 2022 , 179 ( 22 ): 5015 - 5035 .

ZHANG L , SUN L , WANG L R , et al. Mitochondrial division inhibitor (mdivi-1) inhibits proliferation and epithelial-mesenchymal transition via the NF-κB pathway in thyroid cancer cells [J ] . Toxicol In Vitro , 2023 , 88 : 105552 .

RANA A , OLIVEIRA M P , KHAMOUI A V , et al. Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of drosophila melanogaster [J ] . Nat Commun , 2017 , 8 ( 1 ): 448 . DOI: 10.1038/s41467-017-00525-4 http://doi.org/10.1038/s41467-017-00525-4

HU N , CHEN X M , CHEN C C , et al. Exploring the role of esketamine in alleviating depressive symptoms in mice via the PGC-1α/irisin/ERK1/2 signaling pathway [J ] . Sci Rep , 2023 , 13 ( 1 ): 16611 .

HUANG K Y , LIU Z Y , XIE Z L , et al. HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway [J ] . J Transl Med , 2023 , 21 ( 1 ): 253 . DOI: 10.1186/s12967-023-04105-7 http://doi.org/10.1186/s12967-023-04105-7

LIU J F , NING L . Protective role of emodin in rats with post-myocardial infarction heart failure and influence on extracellular signal-regulated kinase pathway [J ] . Bioengineered , 2021 , 12 ( 2 ): 10246 - 10253 . DOI: 10.1080/21655979.2021.1983977 http://doi.org/10.1080/21655979.2021.1983977

LAURIN K M , COUTU-BEAUDRY K , SALAZAR A , et al. Low expression of PGC-1β and other mitochondrial biogenesis modulators in melanoma is associated with growth arrest and the induction of an immunosuppressive gene expression program dependent on MEK and IRF-1 [J ] . Cancer Lett , 2022 , 541 : 215738 .

ASL E R , AMINI M , NAJAFI S , et al. Interplay between MAPK/ERK signaling pathway and microRNAs: a crucial mechanism regulating cancer cell metabolism and tumor progression [J ] . Life Sci , 2021 , 278 : 119499 .

浏览量

1713

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

中国抗癌协会乳腺癌诊治指南与规范（2026年版）

着丝粒蛋白A驱动的染色体不稳定性与乳腺癌相关性研究的进展及展望：机制、预后及临床靶向治疗应用

中国年轻女性乳腺癌发病、死亡近30年的变迁情况及趋势研究

miR-193a-3p通过靶向TRIM14对乳腺癌干细胞迁移和侵袭的影响

乳腺癌新辅助治疗后的腋窝管理及前哨淋巴结诊治的优化