Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression

Duan, Wanxing; Chen, Ke; Jiang, Zhengdong; Chen, Xin; Sun, Liankang; Li, Jiahui; Liu, Jing; Xu, Qinhong; Ma, Jiguang; Li, Xuqi; Han, Liang; Wang, Zheng; Wu, Zheng; Wang, Fengfei; Wu, Erxi; Ma, Qingyong; Ma, Zhenhua

doi:10.1016/j.canlet.2016.10.019

Cited by 86 publications

(85 citation statements)

References 40 publications

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“…We further evaluated its anti-fibrotic role in KPC mice. Similar to our previous report [15], the Masson’s trichrome-stained area was decreased following metformin treatment (Fig. 6f, g).…”

Section: Resultssupporting

confidence: 91%

“…In addition, metformin suppresses TGF-β-induced PSC activation. In accordance with in vitro findings, metformin reduced tumor growth and desmoplasia in subcutaneous and orthotopic models of PDAC [15]. …”

Section: Introductionsupporting

confidence: 86%

“…In addition, metformin use was associated with an improved outcome in diabetic patients with pancreatic cancer [11, 12]. Metformin inhibited pancreatic cancer cell and tumor growth by down-regulating Sp transcriptional factors and showed an impact on the tumor microenvironment in PDAC [13–15]. Our previous study revealed that in human PDAC tissue, AMPK inactivation is correlated with desmoplastic reaction and patients’ poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer.MethodsLSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein.ResultsFollowing metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson’s trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival.ConclusionsMetformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0701-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

Section: Introductionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Images were taken with a microscope (Nikon Instruments Inc.). A Matrigel Transwell assay was used to test cell invasion ability as described in the previous study [22]. Chambers were pre-coated with Matrigel (BD Biosciences, USA).…”

Section: Cell Migration and Invasion Assaysmentioning

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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“…e [13] found that metformin alleviated the fibro-inflammatory microenvironment in obese/diabetic individuals with PC by reprogramming PSCs. Wanxing Duan et al [17] found that metformin induction of AMPK activation represented a novel therapeutic approach for treating advanced PC through desmoplasia suppression. Although the beneficial effect of metformin in a mouse model of PC or in a patient of PC has been demonstrated, an in vivo study to evaluate the effect of AMPK activators on PSCs in pancreas fibrosis is difficult to design and interpret because the effect of AMPK activators can be attributed not only to PSCs but also to major effects on the cancer cell.…”

Section: Discussionmentioning

confidence: 99%

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Wu¹,

Qiu²,

Zhu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

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Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression

Cited by 86 publications

References 40 publications

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

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

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

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

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