Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

Chen, Ke; Qian, Weikun; Jiang, Zhengdong; Liu, Cheng; Li, Jie; Sun, Liankang; Zhou, Cancan; Gao, Luping; Li, Meng; Yan, Bin; Cao, Junyu; Duan, Wanxing; Ma, Qingyong

doi:10.1186/s12943-017-0701-0

Cited by 105 publications

(84 citation statements)

References 52 publications

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“…Of note, senescent cells are highly glycolytic (Moiseeva, Bourdeau, Roux, Deschenes‐Simard, & Ferbeyre, ) suggesting that the defects in this pathway observed in cancer stem cells are acquired during tumor progression. Metformin treatment of mice expressing oncogenic Kras in the pancreas delayed tumorigenesis and decreased the percentage of both early and late PanIN lesions (Chen et al, ). Also, metformin has been shown to target selectively breast and pancreatic cancer cells with stem cell properties (Hirsch et al, ; Sancho et al, ).…”

Section: Discussionmentioning

confidence: 99%

Circumventing senescence is associated with stem cell properties and metformin sensitivity

et al. 2019

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Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene‐induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial‐mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras‐induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.

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Section: Discussionmentioning

confidence: 99%

Circumventing senescence is associated with stem cell properties and metformin sensitivity

et al. 2019

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“…Transgenic pancreatic cancer mouse was introduced as previous described [23]. 20 Kras Pdx1-Cre (KPC) mouse were randomly divided into 2 groups; Control group and SFN treatment group.…”

Section: Transgenic Pancreatic Cancer Mouse and Nude Micementioning

confidence: 99%

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

Chen

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. Methods: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2’-7’-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. Results: SFN can inhibit pancreatic cancer cell growth， promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. Conclusion: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.

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“…As the previous study showed, metformin inhibited autophagy induced by gefitinib and vorinostat whose mechanism had not been clear; in this research, the same phenomenon was observed in osimertinib‐treated NSCLC cells, and metformin combined with osimertinib had a synergistic anti‐tumour effect. Studies have found that the effective mechanism of metformin in cancer cells may be due to cell cycle arrest induction, mTOR inhibition, JAK2/STAT signalling inhibition, immunomodulation, cytotoxic properties and autophagy regulation . Despite both metformin and autophagy inhibitor could inhibit the induction of autophagy, metformin may be a better choice of cancer treatment because of its rich mechanism, metformin co‐treatment with osimertinib probably has more clinical efficiency.…”

Section: Discussionmentioning

confidence: 99%

Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition

Chen

Lin

et al. 2019

Clinical Respiratory J

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Introduction The third‐generation epidermal growth factor receptor (EGFR) inhibitor osimertinib is a promising therapeutic option for patients with advanced non‐small‐cell lung cancer (NSCLC) in second‐line or first‐line treatment because of its applications in selectively inhibiting EGFR T790M and EGFR‐tyrosine kinase inhibitor sensitizing mutations. However, the activation of autophagy associated with osimertinib treatment may play a protective role in NSCLC cells injury induced by osimertinib. Objectives The aim of the present study was to study the effects of the osimertinib‐induced autophagy in NSCLC cells and whether metformin modulates the autophagy and enhances osimertinib sensitivity. Methods The effect of metformin on enhancing osimertinib sensitivity was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, colony formation assay, invasion assay, flow cytometry analysis, western blot analysis and siRNA technique. Results In the present study, we confirmed that osimertinib induced pro‐survival autophagy in H1975 and PC‐9GR cells, and metformin further sensitized H1975 and PC‐9GR cells to osimertinib via inhibiting autophagy. The potential mechanism was that the continual activation of AMPK induced by metformin could inhibit autophagy in a time‐dependent manner. Conclusion Metformin inhibited autophagy and enhanced osimertinib sensitivity via inducing AMPK activation in a time‐dependent manner.

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Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

Cited by 105 publications

References 52 publications

Circumventing senescence is associated with stem cell properties and metformin sensitivity

Circumventing senescence is associated with stem cell properties and metformin sensitivity

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition

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