Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells

Corte, Carminia Maria Della; Ciaramella, Vincenza; Mauro, Concetta Di; Castellone, Maria Domenica; Papaccio, Federica; Fasano, Morena; Sasso, Ferdinando Carlo; Martinelli, Erika; Troiani, Teresa; Vita, Ferdinando De; Orditura, Michele; Bianco, Roberto; Ciardiello, Fortunato

doi:10.18632/oncotarget.6559

Cited by 57 publications

(50 citation statements)

References 41 publications

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“…A study by Kim et al (7) reported that diabetic patients with no administration of insulin had a decreased incidence of gastric cancer when treated with metformin, compared with those who were not treated with metformin. Another previous study showed that the use of metformin as a single agent induced the activation and phosphorylation of mitogen-activated-protein-kinase through the increased heterodimerization of C-RAF/B-RAF in non-small cell lung carcinoma cells (17). In addition, it has been demonstrated that the duration of metformin treatment is associated with the decreased risk of gastric cancer, particularly in patients who used metformin for >3 years (7).…”

Section: Discussionmentioning

confidence: 98%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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Abstract. The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC-27 and MKN-45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma-associated oncogene (Gli)-1, Gli-2 and Gli-3 were examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP-activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli-1 were decreased by metformin treatment in the two cell lines in a dose-and time-dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli-2 and Gli-3. The small interfering RNA-induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh-induced expression of Gli-1 in HGC-27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent. IntroductionGastric cancer is one of the most common types of malignant cancer worldwide (1). In addition tosurgery, chemotherapy and radio chemotherapy, there is a demand for novel treatment approaches for gastric cancer due to its poor prognosis (2).Metformin is a widely used anti-diabetic drug, which has been reported to exhibit potential anticancer activity (3). Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4-6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7). However, the mechanism underlying the anticancer effects of metformin is complex and remains to be fully elucidated. Activation of the AMP-activated protein kinase (AMPK) pathway has been recognized as a key aspect of the anticancer effects of metformin (8).The Sonic hedgehog (Shh) signaling pathway is one of the most common signal transduction pathways in human cells (9). It is critical in normal cell differentiation and embryonic development (10). However, abnormal activation of the Shh pathway has been identified in several types of human cancer (11). Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of m...

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Section: Discussionmentioning

confidence: 98%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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“…Recent reports in tumours suggested that metformin could inhibit cell migration and invasion by suppression of MMP-9 [47][48][49]. A study in skin tissue showed that metformin significantly inhibits MMP-9 expression and protect collagen degradation from solar ultraviolet radiation [50].…”

Section: Discussionmentioning

confidence: 99%

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

Zhang

Tang

Zheng

et al. 2017

J Cellular Molecular Medi

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Blood‐spinal cord barrier (BSCB) disruption is a major process for the secondary injury of spinal cord injury (SCI) and is considered to be a therapeutic target for SCI. Previously, we demonstrated that metformin could improve functional recovery after SCI; however, the effect of metformin on BSCB is still unknown. In this study, we found that metformin could prevent the loss of tight junction (TJ) proteins at day 3 after SCI in vivo, but in vitro there was no significant difference of these proteins between control and metformin treatment in endothelial cells. This indicated that metformin‐induced BSCB protection might not be mediated by up‐regulating TJ proteins directly, but by inhibiting TJ proteins degradation. Thus, we investigated the role of metformin on MMP‐9 and neutrophils infiltration. Neutrophils infiltration is the major source of the enhanced MMP‐9 in SCI. Our results showed that metformin decreased MMP‐9 production and blocked neutrophils infiltration at day 1 after injury, which might be related to ICAM‐1 down‐regulation. Also, our in vitro study showed that metformin inhibited TNF‐α‐induced MMP‐9 up‐regulation in neutrophils, which might be mediated via an AMPK‐dependent pathway. Together, it illustrated that metformin prevented the breakdown of BSCB by inhibiting neutrophils infiltration and MMP‐9 production, but not by up‐regulating TJ proteins expression. Our study may help to better understand the working mechanism of metformin on SCI.

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“…LKB1 interacts with AKT (33), and can facilitate AKT activation and enhance its antiapoptotic effects (33,34). LKB1 and AMPK also exhibit cross talk directly with RAS/RAF/MEK signaling pathways (35,36), in which MEK phosphorylates LKB1, leading to LKB1 and AMPK attenuation, whereas AMPK activation potentiates RAS/RAF/MEK signaling (37). Thus, in LKB1 wild-type cells, metformin and MEK inhibition demonstrate synergistic anticancer effects (37).…”

Section: Discussionmentioning

confidence: 99%

“…LKB1 and AMPK also exhibit cross talk directly with RAS/RAF/MEK signaling pathways (35,36), in which MEK phosphorylates LKB1, leading to LKB1 and AMPK attenuation, whereas AMPK activation potentiates RAS/RAF/MEK signaling (37). Thus, in LKB1 wild-type cells, metformin and MEK inhibition demonstrate synergistic anticancer effects (37). These various pathways exhibit complex feedback and autoregulation, and further studies of these signaling networks will inform understanding of drug sensitivity phenotypes and improve treatment, for example, through the rational design of combinatorial approaches to overcome resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma

et al. 2017

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LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene. In silico screening of drug sensitivity data identified putative LKB1-selective drug candidates, revealing novel associations not apparent from analysis of LKB1 mutations alone. Among the candidates, MEK inhibitors showed robust association with signature expression in both training and testing datasets independent of RAS/RAF mutations. This susceptibility phenotype is directly altered by RNA interference-mediated LKB1 knockdown or by LKB1 re-expression into mutant cell lines and is readily observed in vivo using a xenograft model. MEK sensitivity is dependent on LKB1-induced changes in AKT and FOXO3 activation, consistent with genomic and proteomic analyses of LKB1-deficient lung adenocarcinomas. Our findings implicate the MEK pathway as a potential therapeutic target for LKB1-deficient cancers and define a practical NanoString biomarker to identify functional LKB1 loss. Cancer Res; 77(1); 153-63. ©2016 AACR.

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Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells

Cited by 57 publications

References 41 publications

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma

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