Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang, Song; Wei, Bo; Lu, Canrong; Huang, Xiaohui; Li, Peiyu; Chen, Lin

doi:10.3892/mmr.2017.6205

Cited by 26 publications

(15 citation statements)

References 24 publications

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“…GLI protein expression in tissue samples were examined by western blotting and IHC. In 8 of the 10 cases, both methods revealed that the expression of all GLI proteins was significantly increased in HCC tissues when compared with normal adjacent tissues ( Figures 1A, B ), a finding which is consistent with those for other cancer types, including gastric, colorectal, lung, breast, and pancreatic cancer (Kasper et al, 2006; Lauth and Toftgard, 2007; Song et al, 2017; Didiasova et al, 2018).…”

Section: Resultssupporting

confidence: 81%

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

Zhang¹,

Jiang

et al. 2019

Front. Pharmacol.

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Chemosensitivity is one of the key factors affecting the therapeutic effect on cancer, but the clinical application of corresponding drugs is rare. Hypoxia, a common feature of many solid tumors, including hepatocellular carcinoma (HCC), has been associated with resistance to chemotherapy in part through the activation of the Sonic Hedgehog (SHh) pathway. Hypoxia has also been associated with the increased SUMOylation of multiple proteins, including GLI family proteins, which are key mediators of SHh signaling, and has become a promising target to develop drug-resistant drugs for cancer treatment. However, there are few target drugs to abrogate chemotherapy resistance. Saikosaponin-d (Ssd), one of the main bioactive components of Radix bupleuri, has been reported to exert multiple biological effects, including anticancer activity. Here, we first found that Ssd inhibits the malignant phenotype of HCC cells while increasing their sensitivity to the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) drug system under hypoxia in vitro and in vivo. Furthermore, we had explored that GLI family activation and extensive protein SUMOylation were characteristics of HCC cells, and hypoxia could activate the SHh pathway and promote epithelial-mesenchymal transition (EMT), invasion, and chemosensitivity in HCC cells. SUMOylation is required for hypoxia-dependent activation of GLI proteins. Finally, we found that Ssd could reverse the effects promoted by hypoxia, specifically active sentrin/small ubiquitin-like modifier (SUMO)-specific protease 5 (SENP5), a SUMO-specific protease, in a time- and dose-dependent manner while inhibiting the expression of SUMO1 and GLI proteins. Together, these findings confirm the important role of Ssd in the chemoresistance of liver cancer, provide some data support for further understanding the molecular mechanisms of Ssd inhibition of malignant transformation of HCC cells, and provide a new perspective for the application of traditional Chinese medicine in the chemical resistance of liver cancer.

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Section: Resultssupporting

confidence: 81%

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

Zhang¹,

Jiang

et al. 2019

Front. Pharmacol.

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“… 85 A follow-up study led by the same group showed that both protein and mRNA levels of Shh and Gli 1, Gli2, Gli3 were decreased by metformin in two GC cell lines in a dose- and time-dependent manner. 86 …”

Section: Metformin’s Anti-tumor Effects On Gastric Cancermentioning

confidence: 99%

<p>Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend</p>

Zhang¹,

Wen²,

Zhou³

et al. 2020

CMAR

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Gastric cancer (GC) is a cancer with high prevalence, and is one of the leading causes of cancer death worldwide. Metformin is a widely used hypoglycemic agent for type-2 diabetes mellitus (T2DM). Recently, metformin has drawn increasing attention in the field of cancer research for its emerging anti-cancer roles. However, the efficacy and underlying molecular mechanisms of metformin in the prevention and treatment for GC remain controversial. This review summarized the present clinical and mechanistic studies that investigated the efficacy of metformin in GC. It was found that the majority of clinical studies affirmed protective roles of metformin in both gastric cancer risk and survival rate. In addition, metformin’s effects in the prevention and treatment for GC involve multiple pathways mainly via AMPK and IGF-1R. It was concluded that metformin presents a unique opportunity for application against GC, but further clinical and mechanistic investigations are required to solidify the roles of metformin in GC.

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“…Metformin was reported to directly inhibit mTOR signaling by inactivating Rag GTPases (158), or inducing cell cycle arrest through REDD1, a negative regulator of mTOR (159). Furthermore, several other intracellular effectors were reported to be modulated by metformin treatment to reduce cell proliferation, including, among others, the VEGF/PI3K/Akt pathway (160) in prostate cancer cells, Sonic hedgehog (Shh) signaling pathway in gastric cancer cells (161), inactivation of p38 MAPK and activation of ERK3 (both effects leading to inhibition of mTORC1, in which AMPK was only partially involved) in intrahepatic cholangiocarcinoma cells (162), reversal of the activation of ERK1/2 in ovarian cancer cells (163), inhibition of CLIC1 in gallbladder cancer cells (164); metformin also counterbalanced the overactivation of Notch1/Hes1 signaling observed in colorectal cancer patients (165), and induced apoptosis via the up-regulation of adenosine A1 receptor in human colorectal cancer cells (166). Other putative mechanisms of metformin anti-tumor activity involve the reduced RANKL (167) or caveolin 1 (168) expression in breast CSCs, and HIF-1α gene expression in oral squamous cell carcinoma cell lines, which caused inhibition of cell proliferation and migration (169).…”

Section: Development Of Pharmacological Tools To Target Clic1 Activitmentioning

confidence: 99%

Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity

et al. 2019

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The lack of in-depth knowledge about the molecular determinants of glioblastoma (GBM) occurrence and progression, combined with few effective and BBB crossing-targeted compounds represents a major challenge for the discovery of novel and efficacious drugs for GBM. Among relevant molecular factors controlling the aggressive behavior of GBM, chloride intracellular channel 1 (CLIC1) represents an emerging prognostic and predictive biomarker, as well as a promising therapeutic target. CLIC1 is a metamorphic protein, co-existing as both soluble cytoplasmic and membrane-associated conformers, with the latter acting as chloride selective ion channel. CLIC1 is involved in several physiological cell functions and its abnormal expression triggers tumor development, favoring tumor cell proliferation, invasion, and metastasis. CLIC1 overexpression is associated with aggressive features of various human solid tumors, including GBM, in which its expression level is correlated with poor prognosis. Moreover, increasing evidence shows that modification of microglia ion channel activity, and CLIC1 in particular, contributes to the development of different neuropathological states and brain tumors. Intriguingly, CLIC1 is constitutively active within cancer stem cells (CSCs), while it seems less relevant for the survival of non-CSC GBM subpopulations and for normal cells. CSCs represent GBM development and progression driving force, being endowed with stem cell-like properties (self-renewal and differentiation), ability to survive therapies, to expand and differentiate, causing tumor recurrence. Downregulation of CLIC1 results in drastic inhibition of GBM CSC proliferation in vitro and in vivo, making the control of the activity this of channel a possible innovative pharmacological target. Recently, drugs belonging to the biguanide class (including metformin) were reported to selectively inhibit CLIC1 activity in CSCs, impairing their viability and invasiveness, but sparing normal stem cells, thus representing potential novel antitumor drugs with a safe toxicological profile. On these premises, we review the most recent insights into the biological role of CLIC1 as a potential selective pharmacological target in GBM. Moreover, we examine old and new drugs able to functionally target CLIC1 activity, discussing the challenges and potential development of CLIC1-targeted therapies.

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Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Cited by 26 publications

References 24 publications

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia

<p>Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend</p>

Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity

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