SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

Abstract

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.

Crithmum maritimum Extract Restores Lipid Homeostasis and Metabolic Profile of Liver Cancer Cells to a Normal Phenotype

“…All the other above-mentioned genes are downregulated [29]. Activation of AMPK, SIRT1, and SIRT3 is believed to be a promising option for the prevention and treatment of HCC [30][31][32]. The data reported in Fig.…”

Oxymatrine Improves Oxidative Stress-Induced Senescence in HT22 Cells and Mice via the Activation of AMP-Activated Protein Kinase

“…In addition, AMPK also interacts with SIRT1 to regulate cellular energy metabolism, apoptosis, cell proliferation, and inflammatory responses. SIRT1 is known to directly activate autophagy [55]. Ultimately, AMPK regulates metabolic homeostasis and cell survival during metabolic and oxidative stress [56], and it regulates aging-related transcription factors [57].…”

Understanding the SARS-CoV-2–Human Liver Interactome Using a Comprehensive Analysis of the Individual Virus–Host Interactions

“…One of the transcriptional regulators involved in the response to oxidative stress is HIF1A [69], which remains inactive in normoxic conditions because of its interaction with HIF1AN, an oxygen sensor that hinders interactions with other transcriptional co-activators. SIRT1 serves as an energetic sensor [70], connecting transcriptional regulation to intracellular energetic demands, while TP53BP1 acts as a p53-binding protein, participating in the response to DNA damage.…”