Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways

Truong, Minh; Kim, Hyung Gyun; Khanal, Tilak; Choi, Jae Ho; Kim, Dong Hee; Jeong, Tae Cheon; Jeong, Hye Gwang

doi:10.1016/j.taap.2013.05.010

Cited by 105 publications

(76 citation statements)

References 47 publications

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“…Metformin may also act directly on tumor cells by altering intracellular signaling pathways leading to a decrease in cell proliferation (38)(39)(40)(41)(42)(43). In vitro and animal-based studies have reported that metformin inhibits NSCLC growth by activation of adenosine monophosphate-activated protein kinase in tumor cells (38).…”

Section: Original Articlementioning

confidence: 99%

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Lin

Gallagher

Sigel

et al. 2015

Am J Respir Crit Care Med

121

106

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Rationale: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer.Objectives: To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin.Methods: Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders.Measurements and Main Results: Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P , 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment.Conclusions: Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials.

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Section: Original Articlementioning

confidence: 99%

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Lin

Gallagher

Sigel

et al. 2015

Am J Respir Crit Care Med

121

106

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“…The resulting mutant exhibited 3 point mutations (C (C to A), AGU (U to C), and G (G to U) UUA) as confirmed by sequencing. HO-1-ARE luciferase plasmid contained HO-1 promoter, including the ARE region as described previously [12].…”

Section: Vector Construction and Dual-luciferase Reporter Assaymentioning

confidence: 99%

“…Whole-cell extracts and nuclear extracts were prepared as described previously [12]. The proteins were separated using 10-15% w/v sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and were transferred onto a nitrocellulose membrane (Bio-Rad).…”

Section: Western Blot Analysismentioning

confidence: 99%

MiR-141 Activates Nrf2-Dependent Antioxidant Pathway via Down-Regulating the Expression of Keap1 Conferring the Resistance of Hepatocellular Carcinoma Cells to 5-Fluorouracil

Shi

Wu²,

Chen³

et al. 2015

Cell Physiol Biochem

116

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Background: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. A major cause for the failure of cancer therapy is the development of chemoresistance. Although progress has been made in the study of the mechanisms underlying cancer cells resistance, little is known about the role of microRNAs (miRNAs) in cancer therapy resistance. Methods and Results: Fifteen miRNAs, including 6 up-regulated miRNAs (> 2.0-fold) and 9 down-regulated miRNAs (< 0.5-fold) were differentially expressed in 5-fluorouracil-resistant and their parental cell-lines (HepG2, HepG2/5-FU) by miRNA microarrays. Microarray results were confirmed by validating quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Up-regulation of miR-141 expression resulted in a significant inhibition of 5-FU-mediated cytotoxicity and apoptosis in various hepatocellular carcinoma cells-lines. Mechanically, miR-141 promoted Kelch-like ECH-associated protein 1 (Keap1) mRNA degradation by directly targeting the Keap1 3'untranslated region (3'UTR). Treatment with miR-141 mimics in parental HepG2 cells, restored miR-141 expression and reduced Keap1 levels, thereby resulting in erythroid transcription factor NFE2-L2 (Nrf2) nuclear translocation, activation of Nrf2-dependent HO-1 gene transcription, and subsequent enhancement in 5-FU resistance. Conversely, restoring the expression of Keap1 partly recovered 5-FU sensitivity by counteracting miR-141-mediated 5-FU resistance. Conclusion: Our study showed that miR-141 plays a key role in 5-FU resistance by down-regulating Keap1 expression, thereby reactivating the Nrf2-dependent antioxidant pathway, which may serve as a potential target for overcoming 5-FU resistance in hepatocellular carcinoma cells.

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“…Intriguingly, previous studies predominantly focused on how other drugs may affect the pharmacokinetics of metformin, with limited data available regarding how metformin may influence the metabolism and clearance of other coadministered drugs. Although a known activator of AMPK, metformin appears to exert its pharmacologic actions both AMPK-dependently and -independently (Lee et al, 2012;Do et al, 2013). It also interacts with transcription factors such as the small heterodimer partner, pregnane X receptor (PXR), hepatocyte nuclear factor 4a, and peroxisome proliferatoractivated receptor, which disturb the expression of their target genes thereafter (Prieur et al, 2005;Kim et al, 2008;Krausova et al, 2011;Sozio et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

et al. 2013

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Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase-and extracellular signal-regulated kinase 1/2-dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptorinteracting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates.

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Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways

Cited by 105 publications

References 47 publications

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

MiR-141 Activates Nrf2-Dependent Antioxidant Pathway via Down-Regulating the Expression of Keap1 Conferring the Resistance of Hepatocellular Carcinoma Cells to 5-Fluorouracil

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

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