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SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

BACKGROUND: Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pat...

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Autores principales: Varghese, Benluvankar, Chianese, Ugo, Capasso, Lucia, Sian, Veronica, Bontempo, Paola, Conte, Mariarosaria, Benedetti, Rosaria, Altucci, Lucia, Carafa, Vincenzo, Nebbioso, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504761/
https://www.ncbi.nlm.nih.gov/pubmed/37715252
http://dx.doi.org/10.1186/s12967-023-04440-9
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author Varghese, Benluvankar
Chianese, Ugo
Capasso, Lucia
Sian, Veronica
Bontempo, Paola
Conte, Mariarosaria
Benedetti, Rosaria
Altucci, Lucia
Carafa, Vincenzo
Nebbioso, Angela
author_facet Varghese, Benluvankar
Chianese, Ugo
Capasso, Lucia
Sian, Veronica
Bontempo, Paola
Conte, Mariarosaria
Benedetti, Rosaria
Altucci, Lucia
Carafa, Vincenzo
Nebbioso, Angela
author_sort Varghese, Benluvankar
collection PubMed
description BACKGROUND: Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response. METHODS: Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation. RESULTS: SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6. CONCLUSION: Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04440-9.
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spelling pubmed-105047612023-09-17 SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism Varghese, Benluvankar Chianese, Ugo Capasso, Lucia Sian, Veronica Bontempo, Paola Conte, Mariarosaria Benedetti, Rosaria Altucci, Lucia Carafa, Vincenzo Nebbioso, Angela J Transl Med Research BACKGROUND: Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response. METHODS: Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation. RESULTS: SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6. CONCLUSION: Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04440-9. BioMed Central 2023-09-15 /pmc/articles/PMC10504761/ /pubmed/37715252 http://dx.doi.org/10.1186/s12967-023-04440-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Varghese, Benluvankar
Chianese, Ugo
Capasso, Lucia
Sian, Veronica
Bontempo, Paola
Conte, Mariarosaria
Benedetti, Rosaria
Altucci, Lucia
Carafa, Vincenzo
Nebbioso, Angela
SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title_full SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title_fullStr SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title_full_unstemmed SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title_short SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism
title_sort sirt1 activation promotes energy homeostasis and reprograms liver cancer metabolism
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504761/
https://www.ncbi.nlm.nih.gov/pubmed/37715252
http://dx.doi.org/10.1186/s12967-023-04440-9
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