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Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells
Certain cancer cells prefer aerobic glycolysis rather than oxidative phosphorylation for energy supply. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and regains NAD+ so that glycolysis is continued. As a pivotal enzyme to promote smooth glycolysis, LDHA plays an impo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606903/ https://www.ncbi.nlm.nih.gov/pubmed/36297369 http://dx.doi.org/10.3390/ph15101257 |
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author | Qi, Yuehua Zhang, Chunjing Wu, Di Zhang, Yue Zhao, Yunfeng Li, Wenjuan |
author_facet | Qi, Yuehua Zhang, Chunjing Wu, Di Zhang, Yue Zhao, Yunfeng Li, Wenjuan |
author_sort | Qi, Yuehua |
collection | PubMed |
description | Certain cancer cells prefer aerobic glycolysis rather than oxidative phosphorylation for energy supply. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and regains NAD+ so that glycolysis is continued. As a pivotal enzyme to promote smooth glycolysis, LDHA plays an important role in carcinogenesis. Indole-3-carbinol (I3C) has displayed antitumor activity, but the exact mechanism remains to be identified. In this study, we treated liver cancer cells with I3C, performed colony formation and cell migration, measured the expression of glycolysis-related proteins, and predicted and validated LDHA-targeting miRNA from the databases. In addition, the mRNA and protein levels of p53, glycolysis-related genes and miRNAs that regulate glycolysis were detected after I3C and siRNA-p53 treatment alone or in combination. Next, the expression and colocalization of p53 and MDM2 in liver cancer cells were evaluated after I3C treatment, and the effect of I3C on p53 protein stability was examined. The results showed that I3C inhibited cell proliferation, migration, and the expression levels of glycolysis-related gene LDHAs. MiR-34a was predicted to target LDHA, and I3C downregulated its expression. Furthermore, the combined I3C and siRNA-p53 treatment demonstrated that I3C regulated the expression of LDHA via miR-34a in a p53-dependent manner. Finally, I3C inhibited MDM2 expression and its colocalization with p53 and stabilized p53 expression. In summary, I3C inhibited the degradation of p53 by MDM2 in liver cancer cells; stable p53 induced miR-34a, which targeted LDHA, a key enzyme for aerobic glycolysis, suggesting cancer metabolism is an important target for I3C in liver cancer cells. |
format | Online Article Text |
id | pubmed-9606903 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96069032022-10-28 Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells Qi, Yuehua Zhang, Chunjing Wu, Di Zhang, Yue Zhao, Yunfeng Li, Wenjuan Pharmaceuticals (Basel) Article Certain cancer cells prefer aerobic glycolysis rather than oxidative phosphorylation for energy supply. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and regains NAD+ so that glycolysis is continued. As a pivotal enzyme to promote smooth glycolysis, LDHA plays an important role in carcinogenesis. Indole-3-carbinol (I3C) has displayed antitumor activity, but the exact mechanism remains to be identified. In this study, we treated liver cancer cells with I3C, performed colony formation and cell migration, measured the expression of glycolysis-related proteins, and predicted and validated LDHA-targeting miRNA from the databases. In addition, the mRNA and protein levels of p53, glycolysis-related genes and miRNAs that regulate glycolysis were detected after I3C and siRNA-p53 treatment alone or in combination. Next, the expression and colocalization of p53 and MDM2 in liver cancer cells were evaluated after I3C treatment, and the effect of I3C on p53 protein stability was examined. The results showed that I3C inhibited cell proliferation, migration, and the expression levels of glycolysis-related gene LDHAs. MiR-34a was predicted to target LDHA, and I3C downregulated its expression. Furthermore, the combined I3C and siRNA-p53 treatment demonstrated that I3C regulated the expression of LDHA via miR-34a in a p53-dependent manner. Finally, I3C inhibited MDM2 expression and its colocalization with p53 and stabilized p53 expression. In summary, I3C inhibited the degradation of p53 by MDM2 in liver cancer cells; stable p53 induced miR-34a, which targeted LDHA, a key enzyme for aerobic glycolysis, suggesting cancer metabolism is an important target for I3C in liver cancer cells. MDPI 2022-10-13 /pmc/articles/PMC9606903/ /pubmed/36297369 http://dx.doi.org/10.3390/ph15101257 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Qi, Yuehua Zhang, Chunjing Wu, Di Zhang, Yue Zhao, Yunfeng Li, Wenjuan Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title | Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title_full | Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title_fullStr | Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title_full_unstemmed | Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title_short | Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells |
title_sort | indole-3-carbinol stabilizes p53 to induce mir-34a, which targets ldha to block aerobic glycolysis in liver cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606903/ https://www.ncbi.nlm.nih.gov/pubmed/36297369 http://dx.doi.org/10.3390/ph15101257 |
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