Low glucose enhanced metformin’s inhibitory effect on pancreatic cancer cells by suppressing glycolysis and inducing energy stress via up-regulation of miR-210-5p

Ma, Miling; Ma, Chifa; Li, Pingping; Ma, Chunxiao; Ping, Fan; Li, Wei; Xu, Lingling; Zhang, Huabing; Sun, Qi; Li, Yuxiu

doi:10.1080/15384101.2020.1796036

Cited by 25 publications

(22 citation statements)

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“…MiR-210 is a response binding element of HIF-1α. It has been reported that unstable blood glucose induced energy stress via up-regulating miR-210 in pancreatic cancer cells (35). Our finding provided the evidence that swing of glucose also induced abnormal expression of miR-210 in a mouse glomerular MCs cell line.…”

Section: Discussionsupporting

confidence: 74%

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

Liu

et al. 2021

Front. Med.

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Background and Objective: Glucose fluctuation (GF) has been reported to induce renal injury and diabetic nephropathy (DN). However, the mechanism still remains ambiguous. Mitochondrial energy metabolism, especially aerobic glycolysis, has been a hotspot of DN research for decades. The activation of HIF-1α/miR210/ISCU/FeS axis has provided a new explanation for aerobic glycolysis. Our previous studies indicated quercetin as a potential therapeutic drug for DN. This study aims to evaluate levels of aerobic glycolysis and repressive effect of quercetin via HIF-1α/miR210/ISCU/FeS axis in a cell model of GF.Methods: The mouse glomerular mesangial cells (MCs) were exposed in high or oscillating glucose with or without quercetin treatment. Cell viability was measured by CCK8 assay. Aerobic glycolysis flux was evaluated by lactate acid, pH activity of PFK. Apoptosis level was confirmed by Annexin V-APC/7-AAD double staining and activity of caspase-3. TNF-α and IL-1β were used to evaluate inflammation levels.Results: GF deteriorated inflammation damage and apoptosis injury in MCs, while quercetin could alleviate this GF-triggered cytotoxicity. GF intensified aerobic glycolysis in MCs and quercetin could inhibit this intensification in a dose-dependent manner. Quercetin prevented activities of two FeS-dependent metabolic enzymes, aconitase, and complex I, under GF injury in MCs. The mRNA expression and protein contents of HIF-1α were increased after GF exposure, and these could be alleviated by quercetin treatment. Knockdown of ISCU by siRNA and Up-regulating of miR-210 by mimic could weaken the effects of quercetin that maintained protein levels of ISCU1/2, improved cell viability, relieved inflammation injury, decreased apoptosis, and reduced aerobic glycolysis switch in MCs.Conclusion: Quercetin antagonizes GF-induced renal injury by suppressing aerobic glycolysis via HIF-1α/miR-210/ISCU/FeS pathway in MCs cell model. Our findings contribute to a new insight into understanding the mechanism of GF-induced renal injury and protective effects of quercetin.

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Section: Discussionsupporting

confidence: 74%

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

Liu

et al. 2021

Front. Med.

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“…On the other hand, the potential beneficial effects of lownormal glucose levels has been far less investigated although there is preliminary in-vitro evidence (44,45). Whether efforts aimed at preventing hyperglycemia, either through dietary changes, such as the ketogenic diet (46) or medications, such as metformin, would favorably impact PDAC outcomes remains unclear; one study of metformin plus chemotherapy did not find a benefit (47).…”

Section: Discussionmentioning

confidence: 99%

Glycemic Control as an Early Prognostic Marker in Advanced Pancreatic Cancer

et al. 2021

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PurposeImpaired glucose metabolism is present in most patients with pancreatic ductal adenocarcinoma (PDAC). Whereas previous studies have focused on pre-treatment glycemic indices and prognosis in those with concomitant diabetes, the effects of glycemic control during chemotherapy treatment on prognosis, in patients with and without diabetes, have not been well characterized. We examined the relationship between early glycemic control and overall survival (OS) in a cohort of patients with advanced PDAC treated in a community setting.Patients and MethodsSeventy-three patients with advanced PDAC (38% with diabetes) receiving chemotherapy while participating in a biobanking clinical trial were included. Clinical characteristics and laboratory results during 1 year were obtained from the electronic medical record. Kaplan-Meier estimate, log-rank test and hazard ratios were computed to assess the effect of glycemic control on OS. The Cox proportional hazards regression model was applied to ascertain the significance of glycemic control with other survival variables.ResultsOne thousand four hundred eighteen random blood glucose (RBG) values were analyzed. In accord with previous findings, a 50% decline in the serum tumor marker CA 19-9 at any time was predictive of survival (P=0.0002). In univariate analysis, an elevated pre-treatment average RBG, 3-month average RBG (RBG-3) and the FOLFIRINOX regimen were associated with longer survival. Based on ROC analysis (AUC=0.82), an RBG-3 of 120 mg/dl was determined to be the optimal cutoff to predict 12-month survival. In multivariate analysis that included age, stage, BMI, performance status, presence of diabetes, and chemotherapy regimen, only RBG-3 maintained significance: an RBG-3 ≤120 mg/dl predicted for improved OS compared to >120 mg/dl (19 vs. 9 months; HR=0.37, P=0.002). In contrast, an early decline in CA 19-9 could not predict OS.ConclusionLower glucose levels during the first 3 months of treatment for advanced PDAC predict for improved OS in patients both with and without diabetes. These results suggest that RBG-3 may be a novel prognostic biomarker worthy of confirmation in a larger patient cohort and that studies exploring a possible cause and effect of this novel survival-linked relationship are warranted.

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“…Due to severe reduction of adenosine triphosphate (ATP) production, cancer cells become more susceptive to metformin-induced stress. Consequently, metformin may be more helpful in non-diabetic patients with pancreatic cancer [ 136 ].…”

Section: Pancreatic Cancermentioning

confidence: 99%

How metformin affects various malignancies by means of microRNAs: a brief review

2021

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Metformin known as the first-line orally prescribed drug for lowering blood glucose in type II diabetes (T2DM) has recently found various therapeutic applications including in cancer. Metformin has been studied for its influences in prevention and treatment of cancer through multiple mechanisms such as microRNA (miR) regulation. Alteration in the expression of miRs by metformin may play an important role in the treatment of various cancers. MiRs are single-stranded RNAs that are involved in gene regulation. By binding to the 3′UTR of target mRNAs, miRs influence protein levels. Irregularities in the expression of miRs that control the expression of oncogenes and tumor suppressor genes are associated with the onset and progression of cancer. Metformin may possess an effect on tumor prevention and progression by modifying miR expression and downstream pathways. Here, we summarize the effect of metformin on different types of cancer by regulating the expression of various miRs and the associated downstream molecules.

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Low glucose enhanced metformin’s inhibitory effect on pancreatic cancer cells by suppressing glycolysis and inducing energy stress via up-regulation of miR-210-5p

Abstract: (2020) Low glucose enhanced metformin's inhibitory effect on pancreatic cancer cells by suppressing glycolysis and inducing energy stress via up-regulation

Cited by 25 publications

References 50 publications

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

Glycemic Control as an Early Prognostic Marker in Advanced Pancreatic Cancer

How metformin affects various malignancies by means of microRNAs: a brief review

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