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Zheng JH, Zhu YH, Yang J, Ji PX, Zhao RK, Duan ZH, Yao HF, Jia QY, Yin YF, Hu LP, Li Q, Jiang SH, Huo YM, Liu W, Sun YW, Liu DJ. A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer. Cell Rep 2024; 43:114633. [PMID: 39154343 DOI: 10.1016/j.celrep.2024.114633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 06/19/2024] [Accepted: 07/30/2024] [Indexed: 08/20/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.
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Affiliation(s)
- Jia-Hao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Yu-Heng Zhu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Jian Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Pei-Xuan Ji
- Shanghai Institute of Digestive Disease, Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Rui-Kang Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Zong-Hao Duan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Hong-Fei Yao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Qin-Yuan Jia
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Yi-Fan Yin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Li-Peng Hu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Qing Li
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Shu-Heng Jiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Yan-Miao Huo
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
| | - Wei Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
| | - Yong-Wei Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
| | - De-Jun Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
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Pio-Lopez L, Levin M. Aging as a loss of morphostatic information: A developmental bioelectricity perspective. Ageing Res Rev 2024; 97:102310. [PMID: 38636560 DOI: 10.1016/j.arr.2024.102310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/21/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024]
Abstract
Maintaining order at the tissue level is crucial throughout the lifespan, as failure can lead to cancer and an accumulation of molecular and cellular disorders. Perhaps, the most consistent and pervasive result of these failures is aging, which is characterized by the progressive loss of function and decline in the ability to maintain anatomical homeostasis and reproduce. This leads to organ malfunction, diseases, and ultimately death. The traditional understanding of aging is that it is caused by the accumulation of molecular and cellular damage. In this article, we propose a complementary view of aging from the perspective of endogenous bioelectricity which has not yet been integrated into aging research. We propose a view of aging as a morphostasis defect, a loss of biophysical prepattern information, encoding anatomical setpoints used for dynamic tissue and organ homeostasis. We hypothesize that this is specifically driven by abrogation of the endogenous bioelectric signaling that normally harnesses individual cell behaviors toward the creation and upkeep of complex multicellular structures in vivo. Herein, we first describe bioelectricity as the physiological software of life, and then identify and discuss the links between bioelectricity and life extension strategies and age-related diseases. We develop a bridge between aging and regeneration via bioelectric signaling that suggests a research program for healthful longevity via morphoceuticals. Finally, we discuss the broader implications of the homologies between development, aging, cancer and regeneration and how morphoceuticals can be developed for aging.
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Affiliation(s)
- Léo Pio-Lopez
- Allen Discovery Center, Tufts University, Medford, MA 02155, USA
| | - Michael Levin
- Allen Discovery Center, Tufts University, Medford, MA 02155, USA; Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
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Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med 2023; 21:403. [PMID: 37344841 DOI: 10.1186/s12967-023-04263-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023] Open
Abstract
Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.
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Affiliation(s)
- Yu Hua
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yue Zheng
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
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Ponnalagu D, Hamilton S, Sanghvi S, Antelo D, Schwieterman N, Hansra I, Xu X, Gao E, Edwards JC, Bansal SS, Wold LE, Terentyev D, Janssen PML, Hund TJ, Khan M, Kohut AR, Koch WJ, Singh H. CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection. SCIENCE ADVANCES 2022; 8:eabo1244. [PMID: 36269835 PMCID: PMC9586484 DOI: 10.1126/sciadv.abo1244] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 08/25/2022] [Indexed: 06/12/2023]
Abstract
Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.
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Affiliation(s)
- Devasena Ponnalagu
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Shanna Hamilton
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Shridhar Sanghvi
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Diego Antelo
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Neill Schwieterman
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Inderjot Hansra
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
| | - Xianyao Xu
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- Departments of Biomedical Engineering and Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Erhe Gao
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - John C. Edwards
- Nephrology Division, Department of Internal Medicine, St. Louis University, St. Louis, MO, USA
| | - Shyam S. Bansal
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Loren E. Wold
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Dmitry Terentyev
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Paul M. L. Janssen
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Thomas J. Hund
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- Departments of Biomedical Engineering and Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Mahmood Khan
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- Department of Emergency Medicine, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Andrew R. Kohut
- Penn Heart and Vascular Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Walter J. Koch
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Harpreet Singh
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
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Wu Z, Yu X, Zhang S, He Y, Guo W. The role of PI3K/AKT signaling pathway in gallbladder carcinoma. Am J Transl Res 2022; 14:4426-4442. [PMID: 35958463 PMCID: PMC9360899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/26/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES The prognosis of gallbladder carcinoma (GBC) is poor, with a less than 5% five-year survival rate. Identifying the mechanisms underlying GBC occurrence and advancement is necessary to improve GBC patient prognosis and survival rates. The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (AKT) pathway is involved in cancer deterioration, tumor growth, cell proliferation, and distant metastasis. Studying the impacts of the PI3K/AKT pathway has resulted in the identification of key factors involved in GBC progression that might serve as therapeutic targets, promoting the development of new treatments. METHODS We reviewed recent literature exploring abnormal regulation of the PI3K/AKT pathway in gallbladder cancer, with a focus on abnormal RNA levels, protein level regulation, and drug treatment advances. RESULTS Further investigation of the regulation of small molecules and proteins by the PI3K/AKT pathway might ultimately provide new diagnostic or prognostic markers or cancer treatment targets. Recent studies have focused on RNA and proteins involved in the regulation of the cell cycle or cell movement in cancer progression via PI3K/AKT pathway, the use of anticancer drug combinations, or the anticancer effects of drugs not currently utilized for cancer treatment. CONCLUSIONS We herein review the known available molecules that affect the PI3K/AKT pathway in patients with GBC and the mechanisms of drug action associated with this pathway.
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Affiliation(s)
- Zeyu Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhou 450052, Henan, China
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhou 450052, Henan, China
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhou 450052, Henan, China
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhou 450052, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhou 450052, Henan, China
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhou 450052, Henan, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhou 450052, Henan, China
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhou 450052, Henan, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan UniversitiesZhengzhou 450052, Henan, China
- Henan Key Laboratory of Digestive Organ TransplantationZhengzhou 450052, Henan, China
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Barbieri F, Bosio AG, Pattarozzi A, Tonelli M, Bajetto A, Verduci I, Cianci F, Cannavale G, Palloni LMG, Francesconi V, Thellung S, Fiaschi P, Mazzetti S, Schenone S, Balboni B, Girotto S, Malatesta P, Daga A, Zona G, Mazzanti M, Florio T. Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:53. [PMID: 35135603 PMCID: PMC8822754 DOI: 10.1186/s13046-021-02213-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 12/07/2021] [Indexed: 11/10/2022]
Abstract
Abstract
Background
Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings.
Methods
We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos).
Results
We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity.
Conclusions
These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.
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Wang H, An J, He S, Liao C, Wang J, Tuo B. Chloride intracellular channels as novel biomarkers for digestive system tumors (Review). Mol Med Rep 2021; 24:630. [PMID: 34278487 DOI: 10.3892/mmr.2021.12269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 05/19/2021] [Indexed: 11/06/2022] Open
Abstract
Digestive system malignant tumors are common tumors, and the traditional treatment methods for these tumors include surgical resection, radiotherapy, chemotherapy, and molecularly targeted drugs. However, diagnosis remains challenging, and the early detection of postoperative recurrence is complicated. Therefore, it is necessary to explore novel biomarkers to facilitate clinical diagnosis and treatment. Accumulating evidence supports the crucial role of chloride channels in the development of multiple types of cancers. Given that chloride channels are widely expressed and involved in cell proliferation, apoptosis and cell cycle, among other processes, they may serve as a promising diagnostic and therapeutic target. Chloride intracellular channels (CLICs) are a class of chloride channels that are upregulated or downregulated in certain types of cancer. Furthermore, in certain cases, during cell cycle progression, the localization and function of the cytosolic form of the transmembrane proteins of CLICs are also altered, which may provide a key target for cancer therapy. The aim of the present review was to focus on CLICs as biomarkers for digestive system tumors.
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Affiliation(s)
- Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Suyu He
- The Fourth Department of the Digestive Disease Center, Suining Central Hospital, Suining, Sichuan 629000, P.R. China
| | - Chengcheng Liao
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi, Guizhou 563006, P.R. China
| | - Juan Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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Jiang LL, Liu L. Effect of metformin on stem cells: Molecular mechanism and clinical prospect. World J Stem Cells 2020; 12:1455-1473. [PMID: 33505595 PMCID: PMC7789120 DOI: 10.4252/wjsc.v12.i12.1455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/28/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.
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Affiliation(s)
- Lin-Li Jiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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10
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Tseng CH. Metformin and Biliary Tract Cancer in Patients With Type 2 Diabetes. Front Oncol 2020; 10:587666. [PMID: 33194743 PMCID: PMC7653020 DOI: 10.3389/fonc.2020.587666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/07/2020] [Indexed: 12/13/2022] Open
Abstract
AIM This retrospective cohort study evaluated whether metformin use in patients with type 2 diabetes mellitus might reduce the risk of biliary tract cancer (BTC); and explored whether metformin use might affect the overall survival in patients who developed BTC. METHODS New-onset type 2 diabetes patients aged 25-75 years during 1999-2005 were enrolled from the Taiwan's National Health Insurance and followed up until December 31, 2011. A total of 287,995 ever users and 16,229 never users were identified (unmatched original cohort) and a 1:1 matched pairs of 16,229 ever users and 16,229 never users based on propensity score (PS) were created (matched cohort). Hazard ratios were estimated by three Cox regression models: 1) adjusted for PS; 2) incorporated with the inverse probability of treatment weighting using PS; and 3) all covariates treated as independent variables. Overall survival was compared between ever users and never users of metformin who developed BTC. RESULTS In the unmatched cohort, 73 never users and 523 ever users developed BTC, with respective incidence of 100.36 and 38.06 per 100,000 person-years. An overall risk reduction was observed in metformin users in all three regression models with respective hazard ratio (95% confidence interval) of 0.442 (0.344-0.568), 0.377 (0.295-0.481), and 0.477 (0.370-0.615). The tertile analyses showed a dose-response pattern with a neutral effect in the first tertile when metformin use was <2 years and a significant risk reduction in the second and third tertiles. Findings in the matched cohort were consistent with those observed in the unmatched cohort. The overall survival did not differ significantly between ever and never users of metformin among patients who developed BTC. CONCLUSIONS Metformin significantly reduces the overall risk of BTC by 50%-60%. A dose-response effect is observed and users of approximately 2 years show significantly reduced risk. However, metformin does not affect the overall survival in patients with BTC.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan
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11
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The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer. Cancers (Basel) 2020; 12:cancers12040898. [PMID: 32272658 PMCID: PMC7226178 DOI: 10.3390/cancers12040898] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/01/2020] [Accepted: 04/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.
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12
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Zhang X, Wang Z, Li W, Huang R, Zheng D, Bi G. MicroRNA-217-5p ameliorates endothelial cell apoptosis induced by ox-LDL by targeting CLIC4. Nutr Metab Cardiovasc Dis 2020; 30:523-533. [PMID: 31744714 DOI: 10.1016/j.numecd.2019.09.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 09/24/2019] [Accepted: 09/24/2019] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIMS Endothelial cell apoptosis plays an essential role in the pathogenesis of atherosclerosis. MicroRNAs and chloride intracellular channels (CLICs) have been verified to participate in the endothelial cell apoptosis process, however, the underlying molecular mechanisms are still unclear. The main aim of this study was to investigate the biological effects of microRNA-217-5p (miR-217-5p) and CLIC4 on endothelial cell apoptosis in atherosclerosis. METHODS AND RESULTS An atherosclerotic mouse model (n = 18) was constructed by feeding apolipo protein E knockout ApoE(-/-) mice with high-fat diet for 12 weeks. An atherosclerotic cell model was established by treating human aortic endothelial cells with oxidized low-density lipoprotein (ox-LDL; 50 μg/mL) for 24 h. Quantitative real-time polymerase chain reaction and immunofluorescent staining confirmed the downregulation of miR-217-5p and upregulation of CLIC4 in atherosclerotic endothelial cells. Combined with western blot, flow cytometry assay and Hoechst staining, we demonstrated that miR-217-5p upregulation or CLIC4 knockdown regulated the apoptosis-related genes, ameliorated mitochondrial membrane permeability and therefore inhibited the apoptosis of aortic endothelial cells induced by ox-LDL. We further confirmed that miR-217-5p inhibited apoptosis of endothelial cells through targeting CLIC4 using luciferase report assay and rescue experiments. CONCLUSION We revealed for the first time that miR-217-5p inhibited apoptosis of endothelial cells in atherosclerosis and identified CLIC4 as a novel target of miR-217-5p. Our work provides a potential therapeutic approach for the treatment of atherosclerosis.
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Affiliation(s)
- Xiaotian Zhang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China
| | - Zhimin Wang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China
| | - Weishuai Li
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China
| | - Rui Huang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China
| | - Dongming Zheng
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China
| | - Guorong Bi
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People's Republic of China.
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13
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Gururaja Rao S, Patel NJ, Singh H. Intracellular Chloride Channels: Novel Biomarkers in Diseases. Front Physiol 2020; 11:96. [PMID: 32116799 PMCID: PMC7034325 DOI: 10.3389/fphys.2020.00096] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/27/2020] [Indexed: 12/27/2022] Open
Abstract
Ion channels are integral membrane proteins present on the plasma membrane as well as intracellular membranes. In the human genome, there are more than 400 known genes encoding ion channel proteins. Ion channels are known to regulate several cellular, organellar, and physiological processes. Any mutation or disruption in their function can result in pathological disorders, both common or rare. Ion channels present on the plasma membrane are widely acknowledged for their role in various biological processes, but in recent years, several studies have pointed out the importance of ion channels located in intracellular organelles. However, ion channels located in intracellular organelles are not well-understood in the context of physiological conditions, such as the generation of cellular excitability and ionic homeostasis. Due to the lack of information regarding their molecular identity and technical limitations of studying them, intracellular organelle ion channels have thus far been overlooked as potential therapeutic targets. In this review, we focus on a novel class of intracellular organelle ion channels, Chloride Intracellular Ion Channels (CLICs), mainly documented for their role in cardiovascular, neurophysiology, and tumor biology. CLICs have a single transmembrane domain, and in cells, they exist in cytosolic as well as membranous forms. They are predominantly present in intracellular organelles and have recently been shown to be localized to cardiomyocyte mitochondria as well as exosomes. In fact, a member of this family, CLIC5, is the first mitochondrial chloride channel to be identified on the molecular level in the inner mitochondrial membrane, while another member, CLIC4, is located predominantly in the outer mitochondrial membrane. In this review, we discuss this unique class of intracellular chloride channels, their role in pathologies, such as cardiovascular, cancer, and neurodegenerative diseases, and the recent developments concerning their usage as theraputic targets.
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Affiliation(s)
- Shubha Gururaja Rao
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Neel J Patel
- Department of Cardiology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
| | - Harpreet Singh
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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14
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Zhao K, Wang Z, Li X, Liu JL, Tian L, Chen JQ. Exosome-mediated transfer of CLIC1 contributes to the vincristine-resistance in gastric cancer. Mol Cell Biochem 2019; 462:97-105. [PMID: 31473882 DOI: 10.1007/s11010-019-03613-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 08/17/2019] [Indexed: 12/26/2022]
Abstract
Our previous study shows that high Chloride intracellular channel 1 (CLIC1) expression can efficiently enhance invasion and migration of gastric cancer (GC) cells in vitro. Growing evidences have found that exosomes are involved in chemotherapy resistance in several cancers including GC. We aimed to evaluate the effect of the exosome-mediated transfer of CLIC1 in the vincristine-resistance of GC. The effect of exosome-mediated transfer of CLIC1 on the development of resistance to vincristine in GC cell line SGC-7901 and the potential underlying mechanisms were investigated by Cell Counting Kit-8 (CCK8), RT-PCR, and Western blotting. Exosomes were isolated from cell supernatants by differential ultracentrifugation. Comparing with SGC-7901, the expression level of CLIC1 is higher in vincristine‑resistant cell line SGC-7901/VCR (P < 0.05). After silencing the expression of CLIC1 by RNA interference, the half inhibition concentration (IC50) to vincristine decreased significantly in SGC-7901/VCR, and the expression of CLIC1 decreased significantly in exosomes from SGC-7901/VCR. After 48 h co-culturing with exosomes from SGC-7901/VCR, the IC50 to vincristine in SGC-7901 increased significantly, and the expression of CLIC1, P-gp, and Bcl-2 were significantly up-regulated. CLIC1 was closely associated with the resistance to vincristine in GC, and exosome-mediated transfer of CLIC1 could induce the development of resistance to vincristine in vitro. The possible mechanism was related to up-regulated P-gp and Bcl-2. However, in vivo study was needed to confirm the results in future.
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Affiliation(s)
- Kun Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhen Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Xin Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Jin-Lu Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Lei Tian
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
| | - Jun-Qiang Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
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15
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Barbieri F, Verduci I, Carlini V, Zona G, Pagano A, Mazzanti M, Florio T. Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity. Front Oncol 2019; 9:135. [PMID: 30918838 PMCID: PMC6424887 DOI: 10.3389/fonc.2019.00135] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 02/14/2019] [Indexed: 12/12/2022] Open
Abstract
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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Affiliation(s)
- Federica Barbieri
- Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza per la Ricerca Biomedica, Università di Genoa, Genoa, Italy
| | - Ivan Verduci
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Valentina Carlini
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Gianluigi Zona
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Aldo Pagano
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Dipartimento di Medicina Sperimentale, Università di Genoa, Genoa, Italy
| | - Michele Mazzanti
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Tullio Florio
- Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza per la Ricerca Biomedica, Università di Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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16
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Feng J, Xu J, Xu Y, Xiong J, Xiao T, Jiang C, Li X, Wang Q, Li J, Li Y. CLIC1 promotes the progression of oral squamous cell carcinoma via integrins/ERK pathways. Am J Transl Res 2019; 11:557-571. [PMID: 30899362 PMCID: PMC6413291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 12/21/2018] [Indexed: 06/09/2023]
Abstract
Chloride intracellular channel 1 (CLIC1), a member of the chloride channel protein family, acts as a promoter in many malignancies, but its role in oral cancer remains unclear. Hence, this research aimed to explore the effects of CLIC1 on the progression of oral cancer cells in vitro, and we assessed its role in cell proliferation, apoptosis, migration, invasion, angiogenesis, and chemosensitivity to cisplatin and possible signaling pathways. The results demonstrated that CLIC1 depletion inhibited the proliferation, invasion, migration and angiogenesis of oral squamous cell carcinoma (OSCC) cells in vitro, but promoted cell apoptosis and increased the drug susceptibility to cisplatin. In contrast, CLIC1 upregulation was positively correlated with cell proliferation, invasion and migration and angiogenesis. Mechanistically, CLIC1 silencing decreased the levels of ITGαv, ITGβ1, p-ERK, vimentin, MMP2 and MMP9, and increased the levels of p-p38, E-cadherin, caspase3 and caspase9. CLIC1 overexpression enhanced the ITGαv, ITGβ1, p-ERK, vimentin, MMP2 and MMP9 levels and decreased E-cadherin expression. Overall, these results indicated that CLIC1 promotes the progression of OSCC, and we speculated that its potential mechanism may be related to the regulation of ITGαv and ITGβ1, which led to activation of the MAPK/ERK and MAPK/p38 signal pathways.
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Affiliation(s)
- Jiali Feng
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Jie Xu
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Ying Xu
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Jun Xiong
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Tingting Xiao
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Chao Jiang
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Xian Li
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Qian Wang
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Jie Li
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
| | - Yong Li
- College of Stomatology, Chongqing Medical UniversityChongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical SciencesChongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher EducationChongqing, China
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17
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Xu Y, Xu J, Feng J, Li J, Jiang C, Li X, Zou S, Wang Q, Li Y. Expression of CLIC1 as a potential biomarker for oral squamous cell carcinoma: a preliminary study. Onco Targets Ther 2018; 11:8073-8081. [PMID: 30519049 PMCID: PMC6239106 DOI: 10.2147/ott.s181936] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Purpose CLIC1, a member of the highly conserved class ion-channel protein family, is frequently upregulated in multiple human malignancies and has been demonstrated to play a critical role in cell proliferation, apoptosis, and invasion. However, limited is known about its expression, biological functions, and action mechanism in oral malignancies. We aimed to evaluate whether CLIC1 could be a biomarker for oral squamous cell carcinoma (OSCC). Methods Immunohistochemistry was used to analyze the expression of CLIC1 in tissue. CLIC1 protein and mRNA were measured through Western immunoblotting and quantitative real-time PCR. CLIC1 protein expression in plasma was detected via ELISA. A total of 72 OSCC specimens were recruited in this study for evaluation of correlations of CLIC1 with clinicopathological features and survival. Results CLIC1 was significantly overexpressed in tissue and plasma of OSCC patients. It was found that upregulated CLIC1 was distinctly correlated with histological grade, TNM stage, and tumor size. Meanwhile, Kaplan–Meier survival analysis showed that OSCC patients with high CLIC1 expression had remarkably poorer overall survival rate than those with low CLIC1 expression. Multivariate Cox regression analysis revealed that CLIC1 was the independent prognostic factor for overall survival rate of OSCC patients. In addition, Pearson correlation analysis showed that CLIC1 was associated with multiple tumor-associated genes. Conclusion These results indicated that CLIC1 acts as a molecular target in OSCC and may present a novel diagnostic marker and therapeutic target for OSCC.
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Affiliation(s)
- Ying Xu
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Jie Xu
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Jiali Feng
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Jie Li
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Chao Jiang
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Xian Li
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Sihai Zou
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Qian Wang
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
| | - Yong Li
- College of Stomatology, Chongqing Medical University, Chongqing, China, .,Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China, .,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China,
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18
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Barbieri F, Würth R, Pattarozzi A, Verduci I, Mazzola C, Cattaneo MG, Tonelli M, Solari A, Bajetto A, Daga A, Vicentini LM, Mazzanti M, Florio T. Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability. Front Pharmacol 2018; 9:899. [PMID: 30186163 PMCID: PMC6110922 DOI: 10.3389/fphar.2018.00899] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/23/2018] [Indexed: 12/20/2022] Open
Abstract
The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054–0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanide-structured molecules, characterized by high antitumor efficacy and safe toxicological profile.
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Affiliation(s)
- Federica Barbieri
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Roberto Würth
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Alessandra Pattarozzi
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Ivan Verduci
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Chiara Mazzola
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Maria G Cattaneo
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Michele Tonelli
- Dipartimento di Farmacia, Università di Genova, Genova, Italy
| | - Agnese Solari
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Adriana Bajetto
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Antonio Daga
- IRCCS, Ospedale Policlinico San Martino, Genova, Italy
| | - Lucia M Vicentini
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Michele Mazzanti
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Tullio Florio
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy.,IRCCS, Ospedale Policlinico San Martino, Genova, Italy
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Li H, Jin Y, Hu Y, Jiang L, Liu F, Zhang Y, Hao Y, Chen S, Wu X, Liu Y. The PLGF/c-MYC/miR-19a axis promotes metastasis and stemness in gallbladder cancer. Cancer Sci 2018; 109:1532-1544. [PMID: 29575299 PMCID: PMC5980328 DOI: 10.1111/cas.13585] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/14/2018] [Accepted: 03/17/2018] [Indexed: 12/13/2022] Open
Abstract
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract system. Epithelial-mesenchymal transition (EMT) plays a vital role in the process of tumor metastasis. Mesenchymal-like cells can serve as a source of cancer stem cells, which can confer the EMT phenotype. Placental growth factor (PLGF) belongs to the vascular endothelial growth factor family and plays a vital role in cancer. However, the underlying molecular mechanisms about the influence of PLGF on EMT in GBC remain unknown. Here we show that PLGF expression levels were higher in GBC tissues than in normal adjacent tissues and were associated with poor prognosis in GBC patients. Exogenous PLGF enhanced the migration, invasion, and tumorsphere formation of GBC cells. Conversely, knockdown of PLGF decreased the aggressive phenotype of GBC cells. Mechanistically, exogenous PLGF upregulated microRNA-19a (miR-19a) expression through the activation of c-MYC. Moreover, Spearman's correlation analysis showed a positive pairwise correlation among PLGF, c-MYC, and miR-19a expression in GBC tissues. Taken together, these results suggest that PLGF promotes EMT and tumorsphere formation through inducing miR-19a expression by upregulating c-MYC. Thus, PLGF could be a promising molecular therapeutic target for GBC.
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Affiliation(s)
- Huaifeng Li
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunpeng Jin
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunping Hu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lin Jiang
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fatao Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yijian Zhang
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yajuan Hao
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shili Chen
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiangsong Wu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yingbin Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
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20
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Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects. Sci Rep 2018; 8:3929. [PMID: 29500390 PMCID: PMC5834504 DOI: 10.1038/s41598-018-22054-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 02/16/2018] [Indexed: 12/23/2022] Open
Abstract
Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc+ human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.
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21
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Zhou N, Cheng W, Peng C, Liu Y, Jiang B. Decreased expression of hsa‑miR‑372 predicts poor prognosis in patients with gallbladder cancer by affecting chloride intracellular channel 1. Mol Med Rep 2017; 16:7848-7854. [PMID: 28944858 DOI: 10.3892/mmr.2017.7520] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 07/28/2017] [Indexed: 11/06/2022] Open
Abstract
It has been reported that hsa‑microRNA (miRNA/miR)‑372 functions as a tumor suppressor or oncogene in various digestive system tumors, however, its roles in gallbladder cancer (GBC) are yet to be established. The present study aimed to determine the expression and clinical relevance of hsa‑miR‑372 in GBC. The expression of hsa‑miR‑372 in 80 pairs of human GBC tissues and adjacent normal gallbladder tissues was measured by reverse transcription‑quantitative polymerase chain reaction. Subsequently, the associations between hsa‑miR‑372 expression levels and the clinicopathological characteristics of patients with GBC were determined using χ2 test. Furthermore, Kaplan‑Meier method and Cox regression analysis were performed to evaluate the association between hsa‑miR‑372 expression and the prognosis of patients with GBC. Furthermore, a dual‑luciferase reporter assay and western blot analysis were performed to predict and verify the target gene of hsa‑miR‑372. The results demonstrated that markedly lower hsa‑miR‑372 expression was observed in GBC tissues, which was associated with poor prognosis in patients with GBC. Downregulated expression of hsa‑miR‑372 was negatively associated with tumor histological grade, tumor‑node‑metastasis stage, lymph node metastasis and distant metastasis, however, no association was observed between reduced hsa‑miR‑372 expression and patient gender, age, tumor size and gallbladder stones. Multivariate Cox regression analysis revealed that hsa‑miR‑372 expression, histological grade and lymph node metastasis were independent prognostic factors for overall survival in patients with GBC. Chloride intracellular channel 1 (CLIC1) was previously reported to be an effective biomarker for predicting the prognosis of GBC. Notably, the results of the present study indicated that CLIC1 may be a direct target gene of hsa‑miR‑372. In conclusion, the current study provides the first statistically convincing evidence that downregulation of hsa‑miR‑372 may occur in GBC tissues, which may be associated with aggressive and progressive tumor behavior by affecting CLIC1 expression.
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Affiliation(s)
- Ning Zhou
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Wei Cheng
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Yi Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Bo Jiang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
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22
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Liu Y, Wang Z, Li M, Ye Y, Xu Y, Zhang Y, Yuan R, Jin Y, Hao Y, Jiang L, Hu Y, Chen S, Liu F, Zhang Y, Wu W, Liu Y. Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells. Cancer Sci 2017; 108:1240-1252. [PMID: 28378944 PMCID: PMC5480064 DOI: 10.1111/cas.13248] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 03/27/2017] [Accepted: 03/31/2017] [Indexed: 12/14/2022] Open
Abstract
Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth-suppressive effects on these cell lines via inhibition of p-Akt activity and the Bcl-2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.
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Affiliation(s)
- Yongchen Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zheng Wang
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Maolan Li
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuanyuan Ye
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi Xu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yichi Zhang
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ruiyan Yuan
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunpeng Jin
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yajuan Hao
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lin Jiang
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunping Hu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shili Chen
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fatao Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yijian Zhang
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenguang Wu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yingbin Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua Hospital, Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghaiChina
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