Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK

Satō, Atsushi; Sunayama, Jun; Okada, Masashi; Watanabe, Eriko; Seino, Shizuka; Shibuya, Keita; Suzuki, Kaori; Narita, Yoshitaka; Shibui, Soichiro; Kayama, Takamasa; Kitanaka, Chifumi

doi:10.5966/sctm.2012-0058

Cited by 162 publications

(196 citation statements)

References 36 publications

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“…Moreover, these strong anticancer actions were also supported by Kaplan-Meier analyses, which showed a statistically significant survival benefit. Sato el al 22 observed that metformin treatment alone significantly inhibited tumor growth in an orthotopic mouse model, which was not seen in our experiment. They used the same dose of metformin (500mg/kg) with the same delivery method.…”

Section: Neurooncologymentioning

confidence: 35%

“…18,19 Other research based on the selective toxicity of metformin toward cancer stem cells (CSCs), however, supports a "reverse Warburg effect, " arguing that CSCs are more dependent on oxidative phosphorylation. 15,22,23 Viale et al 20 demonstrated that the surviving cancer cells that are responsible for tumor relapse have features of CSCs and depend on oxidative phosphorylation for their survival.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] Many studies have shown that inhibition of either glycolysis or oxidative phosphorylation is effective to decrease proliferation and invasion of cancer cells. [21][22][23] However, exploiting the idea that simultaneous inhibition of multiple metabolic pathways might be a more effective cancer treatment, several researchers have shown that deprivation of tumor bioenergetics through inhibition of multiple energy pathways could be an effective new therapeutic approach for various human tumors 8,24 -an idea that has not been fully evaluated in a GBM-TS model. Here, we tested the hypothesis that dual inhibition of glycolysis and oxidative phosphorylation effectively and synergistically suppresses GBM-TS in a synergetic manner by evaluating the effect of combined treatment with 2DG and metformin on GBM-TS.…”

mentioning

confidence: 99%

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Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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Background. Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods. Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemnessrelated proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness-and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

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Section: Neurooncologymentioning

confidence: 35%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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“…Mei et al42 further showed that p38 MAPK activation contributes to an increase in CSC population and metastasis. It has been reported that radioresistant glioblastoma stem cells acquired enhanced AMPK activity and in normal human mammary epithelial cells AMPK mediated the mammosphere formation, indicating that AMPK might involve in regulating the self‐renewal and therapeutic resistance of CSCs 38, 39. Our study showed that Sme induced apoptosis via activating the p38 MAPK and AMPKα pathways in MCF7‐Nanog cells.…”

Section: Discussionsupporting

confidence: 49%

“…There is growing evidence supporting that p38 MAPK and AMPK play crucial roles in cancer cell growth, proliferation, survival 38, 39, 40. Meng et al41 reported that p38 MAPK exhibits overexpression in highly metastatic human and mouse breast cancer cell lines and promotes basal‐like and metastatic properties in breast tumor samples.…”

Section: Discussionmentioning

confidence: 99%

Marine sponge‐derived smenospongine preferentially eliminates breast cancer stem‐like cells via p38/AMPKα pathways

Tang

Yang

et al. 2018

Cancer Medicine

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Breast cancer stem cells (CSCs) have been postulated as responsible for therapeutic failure of breast cancer. Novel agents effectively targeting breast CSCs are urging to be discovered to overcome cancer relapse and metastasis. We recently established a CSC‐like model through ectopic expression Nanog, a core pluripotency factor, in breast cancer cells and validated induced CSC‐like (MCF7‐Nanog) model acquired stem‐like properties. Using this model, we found that smenospongine (Sme), a natural sesquiterpene aminoquinone isolated from marine sponge Spongia pertusa Esper, preferentially inhibited the induced CSC‐like cells proliferation by inducing G0/G1 arrest and intrinsic apoptosis via increasing the phosphorylation level of p38 and AMPKα. Importantly, Sme exhibited the ability to abrogate CSC‐like cells associated with a downregulation of stem cell markers including Nanog, Sox2, and Bmi1. Functionally, Sme inhibited the ability of MCF7‐Nanog cells to form tumor sphere in vitro and develop tumor in vivo. Significant antitumor effects are observed in Sme‐treated mouse xenograft tumor models, with no apparent toxicity to mice. Taken together, our findings provide a CSC‐like model to identify novel CSC‐targeting drugs and identify Sme as a candidate natural agent for treatment of breast cancer.

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FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

Pintor,

Lopez,

Flores

et al. 2023

FEBS Open Bio

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Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem‐cell‐like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis (GSEA) indicated that a set of WNT pathway target genes, including lymphoid enhancer‐binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172 and DBTRG upon AS1842856 treatment. In contrast, follow‐up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9‐mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA‐binding‐deficient FOXO1‐H215R. Therefore, FOXO1 induces TCF7 in a DNA‐binding‐independent manner, similar to other published FOXO1‐activated genes such as TCF4 and hes family bHLH transcription factor 1 (HES1). Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T‐cell development and murine acute myeloid leukemia (AML) models.

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Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK

Abstract: MEDICINE 2012;1:811-824

Cited by 162 publications

References 36 publications

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Marine sponge‐derived smenospongine preferentially eliminates breast cancer stem‐like cells via p38/AMPKα pathways

FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

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