Sirtuin 6 and metabolic genes interplay in Warburg effect in cancers

Al‐Azzam, Nosayba

doi:10.3164/jcbn.19-110

Cited by 11 publications

(9 citation statements)

References 89 publications

(128 reference statements)

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“…Similarly, the genetic/epigenetic mechanism for muted inflammatory response in EtOH with sepsis needs to be investigated. Lastly, evidence suggests that SIRT2 is a major metabolic regulator in cancer cells (Al‐Azzam, 2020; Hamaidi et al, 2020). The role of SIRT2 in metabolic perturbations in leukocytes and/or endothelial cells in EtOH with sepsis needs to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Gandhirajan

Roychowdhury

Kibler

et al. 2021

Alcoholism Clin & Exp Res

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Background Sepsis and septic shock kill over 270,000 patients per year in the United States. Sepsis transitions from a hyper‐inflammatory to a hypo‐inflammatory phase. Alcohol dependence is a risk factor for mortality from sepsis. Ethanol (EtOH) exposure impairs pathogen clearance through mechanisms that are not fully understood. Sirtuin 2 (SIRT2) interferes with pathogen clearance in immune cells but its role in the effects of EtOH on sepsis is unknown. We studied the effect of EtOH exposure on hyper‐ and hypo‐inflammation and the role of SIRT2 in mice. Methods We exposed C57Bl/6 (WT) mice to EtOH via drinking water and used intraperitoneal cecal slurry (CS)‐induced sepsis to study: (i) 7‐day survival, (ii) leukocyte adhesion (LA) in the mesenteric microcirculation during hyper‐ and hypo‐inflammation, (iii) peritoneal cavity bacterial clearance, and (iv) SIRT2 expression in peritoneal macrophages. Using EtOH‐exposed and lipopolysaccharide (LPS)‐stimulated RAW 264.7 (RAW) cell macrophages for 4 hours or 24 hours, we studied: (i) tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), and SIRT2 expression, and (ii) the effect of the SIRT2 inhibitor AK‐7 on inflammatory response at 24 hours. Lastly, we studied the effect of EtOH on sepsis in whole body Sirt2 knockout (SIRT2KO) mice during hyper‐ and hypo‐inflammation, bacterial clearance, and 7‐day survival. Results WT EtOH‐sepsis mice showed: (i) Decreased survival, (ii) Muted LA in the microcirculation, (iii) Lower plasma TNF‐α and IL‐6 expression, (iv) Decreased bacterial clearance, and (v) Increased SIRT2 expression in peritoneal macrophages versus vehicle‐sepsis. EtOH‐exposed LPS‐stimulated RAW cells showed: (i) Muted TNF‐α, IL‐6, and increased IL‐10 expression at 4 hours, (ii) endotoxin tolerance at 24 hours, and (iii) reversal of endotoxin tolerance with the SIRT2 inhibitor AK‐7. EtOH‐exposed SIRT2KO‐sepsis mice showed greater 7‐day survival, LA, and bacterial clearance than WT EtOH‐sepsis mice. Conclusion EtOH exposure decreases survival and reduces the inflammatory response to sepsis via increased SIRT2 expression. SIRT2 is a potential therapeutic target in EtOH with sepsis.

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Section: Discussionmentioning

confidence: 99%

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Gandhirajan

Roychowdhury

Kibler

et al. 2021

Alcoholism Clin & Exp Res

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“…Glucose is then phosphorylated by HK to produce glucose-6-phosphate; this is a critical step in glucose metabolism [ 31 ]. Glucose-6-phosphate is subsequently converted into phosphoenol pyruvate through a variety of metabolic enzymes, which is then converted into pyruvate using pyruvate kinase [ 32 ]. Finally, pyruvate is converted to lactate by LDH [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

Shi

Lian

Jia

2022

Evidence-Based Complementary and Alternative Medicine

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Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4′,5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.

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“…Glucose uptake is the first step of the Warburg effect, during which specific membrane transporters such as GLUTs are required (37). This glucose is then phosphorylated by HK to generate glucose-6-phosphate, which is subsequently converted into phosphoenol pyruvate (38), which is then converted into pyruvate by PK, and the pyruvate is finally converted to lactic acid by LDH (39), which is the last step of glycolysis. Inhibiting the activity of GLUTs, HK, PK, and LDH has been shown to suppress the Warburg effect in cancer cells (40,41), thereby modulating their apoptosis, proliferation, Figure 5.…”

Section: Discussionmentioning

confidence: 99%

CRNDE silencing promotes apoptosis and enhances cisplatin sensitivity of colorectal carcinoma cells by inhibiting the Akt/mTORC1‑mediated Warburg effect

et al. 2022

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Colorectal cancer (CRC) is one of the most prevalent gastrointestinal tumors worldwide, with a high mortality rate. The lncRNA colorectal neoplasia differentially expressed (CRNDE) is upregulated in CRC and is involved in regulating the apoptosis, proliferation, and drug sensitivity of CRC cells. However, the specific underlying mechanisms remain to be elucidated. The aim of the present study was to investigate the effects of CRNDE on the Warburg effect in CRC cells, as well as the associated mechanisms. The expression of CRNDE in HCT-116 cells was overexpressed or silenced by transfection. Apoptosis, cisplatin sensitivity, the Warburg effect, and Akt/mTOR activation were evaluated. The results demonstrated that CRNDE inhibition decreased the proliferation and increased the apoptosis and cisplatin sensitivity of HCT-116 cells. In addition, CRNDE inhibition attenuated the Warburg effect in HCT-116 cells, as verified by a decrease in ATP production, lactic acid levels, glucose uptake, and the expression of Warburg effect-related enzymes (GLUT1, LDHA, HK2, and PKM2). CRNDE inhibition also suppressed the activity of the Akt/mTORC1 pathway, as demonstrated by the decreased phosphorylation of Akt, S6K, S6, and mTOR and the increased phosphorylation of 4EBP-1 and EIF-4E. The CRNDE overexpression-induced increase in ATP and lactic acid levels and glucose uptake in HCT-116 cells was reversed by Akt and mTOR inhibitors. These findings indicate that CRNDE silencing promotes apoptosis and enhances cisplatin sensitivity in colorectal carcinoma cells, which may be mediated by the regulation of the Warburg effect via the Akt/mTORC1 pathway. The present study thus provides a potential strategy for the treatment of CRC.

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Sirtuin 6 and metabolic genes interplay in Warburg effect in cancers

Cited by 11 publications

References 89 publications

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression

Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

CRNDE silencing promotes apoptosis and enhances cisplatin sensitivity of colorectal carcinoma cells by inhibiting the Akt/mTORC1‑mediated Warburg effect

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