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Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation
Background: Shikonin, a small molecule inhibitor of pyruvate kinase 2 (PKM2), has been demonstrated to play the antitumor effect in various cancers. However, the specific effects and related regulatory mechanism of Shikonin in esophageal squamous cell carcinoma (ESCC) have not been clearly declared....
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247391/ https://www.ncbi.nlm.nih.gov/pubmed/34234853 http://dx.doi.org/10.7150/jca.58494 |
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author | Zhang, Qiqi Liu, Qing Zheng, Shutao Liu, Tao Yang, Lifei Han, Xiujuan Lu, Xiaomei |
author_facet | Zhang, Qiqi Liu, Qing Zheng, Shutao Liu, Tao Yang, Lifei Han, Xiujuan Lu, Xiaomei |
author_sort | Zhang, Qiqi |
collection | PubMed |
description | Background: Shikonin, a small molecule inhibitor of pyruvate kinase 2 (PKM2), has been demonstrated to play the antitumor effect in various cancers. However, the specific effects and related regulatory mechanism of Shikonin in esophageal squamous cell carcinoma (ESCC) have not been clearly declared. Materials and methods: Cell viability was valued through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity were measured using corresponding assay kits. Patient-derived xenograft (PDX) models were constructed to observe the anti-ESCC effect of Shikonin in vivo. PKM2, p-PKM2, signal transducer and activator of transcription 3 (STAT3), p-STAT3, glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) in ESCC tissues were assessed by western blot. The expression of PKM2, p-PKM2, p-STAT3, GLUT1 and HK2 was assessed by immunohistochemistry (IHC) in ESCC tissue based on PDXs. Results: Shikonin effectively inhibited cell proliferation in dose-dependent and time-dependent manner compared with the control group. The detection of glycolysis showed that Shikonin suppressed the glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity. Furthermore, Shikonin not only inhibited the growth of ESCC, but also decreased the expression of p-PKM2 and p-STAT3 in vivo. Finally, Shikonin suppressed the expression of GLUT1 and HK2 proteins which are related to glycolysis. Conclusion: Shikonin has a significant antitumor effect in the ESCC by suppressing PKM2 mediated aerobic glycolysis and regulating PKM2/STAT3 signal pathway. |
format | Online Article Text |
id | pubmed-8247391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-82473912021-07-06 Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation Zhang, Qiqi Liu, Qing Zheng, Shutao Liu, Tao Yang, Lifei Han, Xiujuan Lu, Xiaomei J Cancer Research Paper Background: Shikonin, a small molecule inhibitor of pyruvate kinase 2 (PKM2), has been demonstrated to play the antitumor effect in various cancers. However, the specific effects and related regulatory mechanism of Shikonin in esophageal squamous cell carcinoma (ESCC) have not been clearly declared. Materials and methods: Cell viability was valued through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity were measured using corresponding assay kits. Patient-derived xenograft (PDX) models were constructed to observe the anti-ESCC effect of Shikonin in vivo. PKM2, p-PKM2, signal transducer and activator of transcription 3 (STAT3), p-STAT3, glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) in ESCC tissues were assessed by western blot. The expression of PKM2, p-PKM2, p-STAT3, GLUT1 and HK2 was assessed by immunohistochemistry (IHC) in ESCC tissue based on PDXs. Results: Shikonin effectively inhibited cell proliferation in dose-dependent and time-dependent manner compared with the control group. The detection of glycolysis showed that Shikonin suppressed the glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity. Furthermore, Shikonin not only inhibited the growth of ESCC, but also decreased the expression of p-PKM2 and p-STAT3 in vivo. Finally, Shikonin suppressed the expression of GLUT1 and HK2 proteins which are related to glycolysis. Conclusion: Shikonin has a significant antitumor effect in the ESCC by suppressing PKM2 mediated aerobic glycolysis and regulating PKM2/STAT3 signal pathway. Ivyspring International Publisher 2021-06-11 /pmc/articles/PMC8247391/ /pubmed/34234853 http://dx.doi.org/10.7150/jca.58494 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Zhang, Qiqi Liu, Qing Zheng, Shutao Liu, Tao Yang, Lifei Han, Xiujuan Lu, Xiaomei Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title | Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title_full | Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title_fullStr | Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title_full_unstemmed | Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title_short | Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation |
title_sort | shikonin inhibits tumor growth of escc by suppressing pkm2 mediated aerobic glycolysis and stat3 phosphorylation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247391/ https://www.ncbi.nlm.nih.gov/pubmed/34234853 http://dx.doi.org/10.7150/jca.58494 |
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