• Glycolysis
• KLF5
• Ovarian Cancer
• PI3K/AKT Signaling Pathway
• Ursolic Acid

• Triterpenes/pharmacology
• Female
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/genetics
• Ursolic Acid
• Glycolysis/drug effects
• Humans
• Signal Transduction/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Kruppel-Like Transcription Factors/metabolism
• Kruppel-Like Transcription Factors/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Cell Proliferation/drug effects
• Apoptosis/drug effects
• Animals
• Cisplatin/pharmacology
• Antineoplastic Agents, Phytogenic/pharmacology
• Cell Line, Tumor
• Phytotherapy
• Mice

• ROS
• SIRT2
• isobavachalcone
• triple‐negative breast cancer

• Humans
• Sirtuin 2/pharmacology
• Cell Line, Tumor
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/pathology
• Tubulin/pharmacology
• Tubulin/therapeutic use
• Cell Proliferation
• Apoptosis
• Chalcones

• 82174193 National Natural Science Foundation of China
• 82374245 National Natural Science Foundation of China
• U19A2010 National Natural Science Foundation of China
• 202001BA070001-057 Science and Technology Plan Project of Yunnan Province
• 2022JDJQ0058 Natural Science Foundation of Sichuan Province
• 2022NSFSC1535 Natural Science Foundation of Sichuan Province
• QNXZ2018007 Xinglin Scholar Talent Research Supporting Program of CDUTCM
• QNXZ2018011 Xinglin Scholar Talent Research Supporting Program of CDUTCM

• Bioinformatics analysis
• Cholangiocarcinoma
• Clinical significance
• Prognostic model
• Silence information regulator 2

• Humans
• Bile Duct Neoplasms/surgery
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma/surgery
• Prognosis
• Sirtuin 2

• SET domain containing 5
• gastric cancer
• glucose consumption
• glycolysis
• proliferation

• Acetylation
• Cholangiocarcinoma
• DNA methylation
• Deacetylation
• Epigenetic
• Noncoding RNAs

• Humans
• Epigenesis, Genetic
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/pathology
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Bile Ducts/pathology
• Bile Ducts, Intrahepatic/pathology

• exosome
• glioma
• hypoxia inducible factor 1α
• microRNA 29a‑3p

• biomarker
• cholangiocarcinoma
• immune microenvironment
• necroptosis
• prognostic signature

• Humans
• Necroptosis/genetics
• Prognosis
• Cholangiocarcinoma/genetics
• Bile Duct Neoplasms/genetics
• Bile Ducts, Intrahepatic
• Biomarkers

• CD36
• IDH1/2
• PGC1α
• cancer stem cells
• fatty acid synthase
• fatty acids
• glutamine
• glycolysis
• mTOR
• methionine adenosyltransferases
• mitochondria
• oxidative metabolism

Erlotinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Overcoming erlotinib resistance is crucial to improve the survival of advanced non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. It is also an important clinical problem that urgently needs a solution. In this study, we explored strategies to overcome erlotinib resistance from the perspective of energy metabolism. SIRT6 is a histone deacetylase. Here, we found that high expression of SIRT6 is associated with poor prognosis of lung adenocarcinoma, especially in EGFR-mutated NSCLC patients. The next cell experiment found that SIRT6 expression increased in erlotinib-resistant cells, and SIRT6 expression was negatively correlated with the sensitivity of NSCLC to erlotinib. Inhibition of SIRT6 promoted erlotinib-induced apoptosis in erlotinib-resistant cells, and glycolysis in drug-resistant cells was also inhibited. Functional studies have shown that SIRT6 increases glycolysis through the HIF-1α/HK2 signaling axis in drug-resistant cells and inhibits the sensitivity of NSCLC cells to erlotinib. In addition, the HIF-1α blocker PX478-2HCL attenuated the glycolysis and erlotinib resistance induced by SIRT6. More importantly, we confirmed the antitumor effect of SIRT6 inhibition combined with erlotinib in NSCLC-bearing mice. Our findings indicate that the cancer metabolic pathway regulated by SIRT6 may be a new target for attenuating NSCLC erlotinib resistance and has potential as a biomarker or therapeutic target to improve outcomes in NSCLC patients.

• EGFR-TKI
• Erlotinib
• Glycolysis
• NSCLC
• SIRT6

Esophageal cancer (EC) is a malignant cancer that still has a poor prognosis, although its prognosis has been improving with the development of multidisciplinary treatment modalities such as surgery, chemotherapy and radiotherapy. Therefore, identifying specific molecular markers that can be served as biomarkers for the prognosis and treatment response of EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent proteins consisting of seven members (SIRT1-7). These proteins have been reported to be involved in the regulation of a variety of biological functions including apoptosis, metabolism, stress response, senescence, differentiation and cell cycle progression. Given the variety of functions of sirtuins, they are speculated to be associated in some manner with cancer progression. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancer-promoting and cancer-suppressing properties, depending on the type of cancer. These conflicting characteristics make research into the nature of sirtuins all the more fascinating. However, the role of sirtuins in EC remains unclear due to the limited number of reports concerning sirtuins in EC. We herein review the current findings and future prospects of sirtuins in EC.

• Esophageal cancer
• Sirtuin
• Esophageal squamous cell carcinoma
• Esophageal adenocarcinoma
• Biomarker
• Treatment

• Cancer stem cells
• Molecular markers
• Stem cell origin

• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplastic Stem Cells/pathology
• Cell Differentiation
• Phenotype
• Tumor Microenvironment/genetics

• Apoptosis
• Label-free proteomics
• Lipocalin 2

In the last decade, metabolic reprogramming has emerged as a driving characteristic of cancer cells. The MYC oncogene, a transcription factor, has become of growing interest as a fundamental driver of differential cancer cell metabolism. Furthermore, the non-essential amino acid glutamine is deemed to be an important nutrient for cancer cells. In fact, glutamine can integrate into a wide variety of metabolic pathways, from energy metabolism to nucleotide synthesis. This review offers a comprehensive and specific overview of recent discoveries in the regulation of MYC oncogene activation on glutamine metabolism in cancer cells.

Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

• MYC
• glutamine metabolism
• oncogene

• Central Nervous System Neoplasms
• Child
• Cohort Studies
• Glioma
• Single Nucleotide Polymorphism

The regulatory relationship between silent information regulator 2 (SIRT2) and glucose 6‐phosphate dehydrogenase (G6PD) in clear cell renal cell carcinoma (ccRCC) is still unclear. The present study aimed to explore the function of SIRT2 and its regulatory effect on G6PD in ccRCC. The Cancer Genome Atlas data mining of SIRT2 was first analyzed. Quantitative real‐time PCR and western blot analyses were used to assess the mRNA and protein expression levels, respectively. Cell viability, colony formation, cell cycle, cell apoptosis, and TUNEL assays and EdU staining were used to investigate the roles of SIRT2 in ccRCC proliferation and apoptosis. The coimmunoprecipitation (Co‐IP) assay was used to analyze the association between SIRT2 and G6PD in ccRCC cells. Quantitative Co‐IP assay was used to detect the levels of G6PD ubiquitination and small ubiquitin‐related modifier 1 (SUMO1). An in vivo experiment was also carried out to confirm in vitro findings. The results indicated that SIRT2 promoted ccRCC proliferation and inhibited apoptosis by regulating cell cycle and apoptosis related proteins. Silent information regulator 2 interacted with G6PD, facilitated its activity through deacetylation, and increased its stability by reducing its ubiquitination and enhancing its SUMO1 modification. Silent information regulator 2 also promoted ccRCC tumor development in vivo. Taken together, the present study indicated that SIRT2 promoted ccRCC progression by increasing G6PD activity and stability, and it could be a potential new diagnostic and therapeutic target for ccRCC.

• G6PD
• SIRT2
• SUMO1
• clear cell renal cell carcinoma
• deacetylation

• cancer microenvironment
• oncogenes
• tumour immunology
• melanoma

• Animals
• Biomarkers
• Cell Line, Tumor
• Cell Movement
• Disease Progression
• Immunomodulation
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Lymphocytes, Tumor-Infiltrating/pathology
• Melanoma/etiology
• Melanoma/metabolism
• Melanoma/pathology
• Melanoma, Experimental
• Mice
• Sirtuin 2/genetics
• Sirtuin 2/metabolism
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

• R01 CA188500 NIH HHS
• R01 AI129582 NIAID NIH HHS
• R01 CA188500 NCI NIH HHS
• R01 CA185301 NCI NIH HHS
• R01 NS106170 NINDS NIH HHS
• R21 CA223400 NCI NIH HHS
• R01 CA247550 NCI NIH HHS
• R01 CA265095 NCI NIH HHS
• P01 CA163205 NCI NIH HHS
• R01 CA163838 NCI NIH HHS
• National Institutes of Health

• Animals
• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/metabolism
• CCAAT-Enhancer-Binding Proteins/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/metabolism
• DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
• DNA (Cytosine-5-)-Methyltransferase 1/metabolism
• DNA Methylation/drug effects
• DNA Methylation/physiology
• Enzyme Inhibitors/pharmacology
• Epigenesis, Genetic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Histocompatibility Antigens/metabolism
• Histone Code/drug effects
• Histone Code/physiology
• Histone-Lysine N-Methyltransferase/antagonists & inhibitors
• Histone-Lysine N-Methyltransferase/metabolism
• Humans
• Mice
• Treatment Outcome
• Ubiquitin-Protein Ligases/metabolism
• Xenograft Model Antitumor Assays/methods

The prevention and treatment of cancer is an ongoing medical challenge. In the context of personalized medicine, the well-studied polyphenol resveratrol could complement classical tumor therapy. It may affect key processes such as inflammation, angiogenesis, proliferation, metastasis, glucose metabolism, and apoptosis in various cancers because resveratrol acts as a multi-targeting agent by modulating multiple signal transduction pathways. This review article focuses on resveratrol’s ability to modify tumor glucose metabolism and its associated therapeutic capacity. Resveratrol reduces glucose uptake and glycolysis by affecting Glut1, PFK1, HIF-1α, ROS, PDH, and the CamKKB/AMPK pathway. It also inhibits cell growth, invasion, and proliferation by targeting NF-kB, Sirt1, Sirt3, LDH, PI-3K, mTOR, PKM2, R5P, G6PD, TKT, talin, and PGAM. In addition, resveratrol induces apoptosis by targeting integrin, p53, LDH, and FAK. In conclusion, resveratrol has many potentials to intervene in tumor processes if bioavailability can be increased and this natural compound can be used selectively.

Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.

• anti-tumor action
• combinatorial therapy
• resveratrol
• tumor glucose metabolism
• warburg phenomenon

• Amelanotic melanoma
• Apoptosis
• Cell death
• Chloroacridine
• Melanotic melanoma
• Tricarboxylic acid cycle enzymes

• Lipogenesis
• SIRT2
• miR-212
• miR-375
• miR-655

• aerobic glycolysis
• cholangiocarcinoma
• glucose metabolism
• metabolic reprogramming
• warburg effect

• Bile Duct Neoplasms/blood supply
• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/enzymology
• Cholangiocarcinoma/blood supply
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/enzymology
• Clinical Trials as Topic
• Gene Expression Regulation, Neoplastic/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylases/genetics
• Histone Deacetylases/metabolism
• Humans
• Molecular Targeted Therapy
• Prognosis
• Survival Analysis
• Treatment Outcome

• HDACi
• HDACs
• cholangiocarcinoma
• hepatobiliary cancers

• Acetylation
• Biological Products/pharmacology
• Biological Products/therapeutic use
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/enzymology
• Cholangiocarcinoma/pathology
• Histone Deacetylases/metabolism
• Humans
• Models, Biological

• R01 CA183764 NCI NIH HHS

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

• OXPHOS
• PGC-1α
• cholangiocarcinoma
• fatty acid synthase
• fatty acids
• mitochondria
• tricarboxylic acid cycle

Sirtuins compose a unique collection of histone deacetylase enzymes that have a wide variety of enzymatic activities and regulate diverse cell functions such as cellular metabolism, longevity and energy homeostasis, mitochondrial function, and biogenesis. Impaired sirtuin functions or alterations of their expression levels may result in several pathological conditions and contribute to the altered metabolic phenotype of malignantly transformed cells in a significant manner. In the twenty-first century, principles of personalized anticancer treatment need to involve not only the evaluation of changes of the genetic material, but also the mapping of epigenetic and metabolic alterations, to both of which the contribution of sirtuin enzymes is fundamental. Since sirtuins are central players in the maintenance of cellular energy and metabolic homeostasis, they are key elements in the development of metabolic transformation of cancer cells referred to as the Warburg effect. Although its most well-known features are enhanced glycolysis and excessive lactate production, Warburg effect has several aspects involving both carbohydrate, lipid, and amino acid metabolism, among which different tumor types have different preferences. Therefore, energy supply of cancer cells can be impaired by a growing number of antimetabolite agents, for which appropriate vectors are strongly needed. However, data are controversial about their tumor suppressor or oncogenic properties, the biological effects of sirtuin enzymes strongly depend on the tissue microenvironment (TME) in which they are expressed. Immune cells are regarded as key players of TME. Sirtuins regulate the survival, activation, metabolism, and mitochondrial function of these cells, therefore, they are not only single elements, but key regulators of the network that determines anticancer immunity. Altered metabolism of tumor cells induces changes in the gene expression pattern of cells in TME, due to altered concentrations of metabolite cofactors of epigenetic modifiers including sirtuins. In summary, epigenetic and metabolic alterations in malignant diseases are influenced by sirtuins in a significant manner, and should be treated in a personalized approach. Since they often develop in early stages of cancer, broad examination of these alterations is required at time of the diagnosis in order to provide a personalized combination of distinct therapeutic agents.

• cancer
• epigenetics
• metabolism
• personalized treatment
• sirtuin enzymes

• Sirtuins
• apoptosis
• cell viability
• metastasis
• tumorigenesis