S'abonner

PLK1 regulating chemoradiotherapy sensitivity of esophageal squamous cell carcinoma through pentose phosphate pathway/ferroptosis - 11/11/23

Doi : 10.1016/j.biopha.2023.115711 
Mengnan Zhao a, 1, Tao Lu a, b, 1, Guoshu Bi a, 1, Zhengyang Hu a, Jiaqi Liang a, Yunyi Bian a, Mingxiang Feng a, , Cheng Zhan a,
a Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China 
b Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University 

Corresponding authors.

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is the most common pathological type of esophageal cancer in China, accounting for more than 90 %. Most patients were diagnosed with advanced-stage ESCC, for whom new adjuvant therapy is recommended. Therefore, it is urgent to explore new therapeutic targets for ESCC. Ferroptosis, a newly discovered iron-dependent programmed cell death, has been shown to play an important role in carcinogenesis by many studies. This study explored the effect of Polo like kinase 1 (PLK1) on chemoradiotherapy sensitivity of ESCC through ferroptosis

Methods

In this study, we knocked out the expression of PLK1 (PLK1-KO) in ESCC cell lines (KYSE150 and ECA109) with CRISPR/CAS9. The effects of PLK1-knock out on G6PD, the rate-limiting enzyme of pentose phosphate pathway (PPP), and downstream NADPH and GSH were explored. The lipid peroxidation was observed by flow cytometry, and the changes in mitochondria were observed by transmission electron microscopy. Next, through the CCK-8 assay and clone formation assay, the sensitivity to cobalt 60 rays, paclitaxel, and cisplatin were assessed after PLK1-knock out, and the nude mouse tumorigenesis experiment further verified it. The regulation of transcription factor YY1 on PLK1 was evaluated by dual luciferase reporter assay. The expression and correlation of PLK1 and YY1, and their impact on prognosis were analyzed in more than 300 ESCC cases from the GEO database and our center. Finally, the above results were further proved by single-cell sequencing.

Results

After PLK1 knockout, the expression of G6PD dimer and the level of NADPH and GSH in KYSE150 and ECA109 cells significantly decreased. Accordingly, lipid peroxidation increased, mitochondria became smaller, membrane density increased, and ferroptosis was more likely to occur. However, with the stimulation of exogenous GSH (10 mM), there was no significant difference in lipid peroxidation and ferroptosis between the PLK1-KO group and the control group. After ionizing radiation, the PLK1-KO group had higher lipid peroxidation ratio, more cell death, and was more sensitive to radiation, while exogenous GSH (10 mM) could eliminate this difference. Similar results could also be observed when receiving paclitaxel combined with cisplatin and chemoradiotherapy. The expression of PLK1, G6PD dimer, and the level of NADPH and GSH in KYSE150, ECA109, and 293 T cells stably transfected with YY1-shRNAs significantly decreased, and the cells were more sensitive to radiotherapy and chemotherapy. ESCC patients from the GEO database and our center, YY1 and PLK1 expression were significantly positively-correlated, and the survival of patients with high expression of PLK1 was significantly shorter. Further analysis of single-cell sequencing specimens of ESCC in our center confirmed the above results.

Conclusion

In ESCC, down-regulation of PLK1 can inhibit PPP, and reduce the level of NADPH and GSH, thereby promoting ferroptosis and improving their sensitivity to radiotherapy and chemotherapy. Transcription factor YY1 has a positive regulatory effect on PLK1, and their expressions were positively correlated. PLK1 may be a target for predicting and enhancing the chemoradiotherapy sensitivity of ESCC.

Le texte complet de cet article est disponible en PDF.

Graphical Abstract




ga1

Le texte complet de cet article est disponible en PDF.

Highlights

PLK1 inhibits ferroptosis of ESCC by promoting the pentose phosphate pathway.
Down-regulation of PLK1 improves the sensitivity of ESCC to chemoradiotherapy.
YY1 positively regulates the expression of PLK1.
YY1 and PLK1 are overexpressed in cancer cells of ESCC.

Le texte complet de cet article est disponible en PDF.

Abbreviations : ESCC,, PLK1,, PPP,, GSH,, scRNA-seq,, HEK293T,, SDS-PAGE,, PVDF,, HRP,, PBS,, CCK-8,, FFPE,, TSA,, CNVs,

Keywords : Esophageal squamous cell carcinoma, Chemoradiotherapy, PLK1, Ferroptosis, Single-cell transcriptome sequencing


Plan


© 2023  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

  • Contenu

Vol 168

Article 115711- décembre 2023 Retour au numéro
Article précédent Article précédent
  • Bruceine A: Suppressing metastasis via MEK/ERK pathway and invoking mitochondrial apoptosis in triple-negative breast cancer
  • Xiao Li, Changqun Liu, Xin Zhang, Chen Sun, Jie Ling, Yilan Liu, Yi Zuo, Yuening Cao, Chaozheng Zhang, Tao Jiang, Maolin Wang, Jin Liu, Jun Lu
| Article suivant Article suivant
  • Combination of curcumin and catalase protects against chondrocyte injury and knee osteoarthritis progression by suppressing oxidative stress
  • Bohao Chen, Qi He, Chuyi Chen, Yuewei Lin, Jiacong Xiao, Zhaofeng Pan, Miao Li, Shaocong Li, Junzheng Yang, FanChen Wang, Jiaxu Zeng, Yanzi Yi, Weijin Chi, Kai Meng, Haibin Wang, Peng Chen

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

Mon compte


Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.


Tout le contenu de ce site: Copyright © 2024 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.