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Dimou J, D'Abaco G, Paradiso L, Kountouri N, Ng W, Stylli S, Drummond K, Burgess A, Kaye A, Morokoff A. Akt inhibition is effective against PTEN-deleted, chemoirradiation-resistant glioblastoma stem cells. Growth Factors 2025; 43:20-36. [PMID: 40078116 DOI: 10.1080/08977194.2025.2470185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
Activated Akt and loss of phosphatase and tensin homolog (PTEN) tumour suppression aid chemo- and radio-resistance in glioblastoma stem cells (GSC), contributing to treatment failure in glioblastoma. In this study, sixteen GSC lines were generated from 66 individual glioma samples, in gliomasphere culture conditions. Thirteen of 16 GSC lines expressed hyperphosphorylated Akt (Ser473); Akt phosphorylation did not correlated with EGFR expression. An LDH colorimetric assay was used to measure the in vitro cytotoxicity of eight of these lines. Akt X (20 µM) proved more effective at inducing in vitro GSC cytotoxicity (range: 22-73%) over 48 hours than triciribine (20 µM) (0-27%), although both agents inhibited Akt phosphorylation as detected by western blot analysis. A statistically significant correlation between PTEN loss (western blot) and the extent of Akt X-induced cytotoxicity was found (p = 0.03). Akt inhibition reduces in vitro proliferation of treatment-resistant GSC lines, especially in PTEN-deficient lines, warranting further translational investigation in glioblastoma.
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Affiliation(s)
- James Dimou
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Giovanna D'Abaco
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Lucy Paradiso
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Nicole Kountouri
- Department of Surgery, The University of Melbourne, Parkville, Australia
| | - Wayne Ng
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Stanley Stylli
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Katharine Drummond
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Antony Burgess
- Department of Structural Biology, Walter and Eliza Hall Institute, Parkville, Australia
| | - Andrew Kaye
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
| | - Andrew Morokoff
- Department of Surgery, The University of Melbourne, Parkville, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Australia
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2
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Chen J, Wang Y, Huang J, Yang Z, Niu H, Su X, Huang J, Ma H, Zhu Y, Wu C, Shi J. Cascade specific endogenous Fe 3+ interference and in situ catalysis for tumor therapy with stemness suppression. Natl Sci Rev 2025; 12:nwae434. [PMID: 39967605 PMCID: PMC11833684 DOI: 10.1093/nsr/nwae434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/03/2024] [Accepted: 11/26/2024] [Indexed: 02/20/2025] Open
Abstract
Cancer stem-like cells (CSCs), featuring high tumorigenicity and invasiveness, are one of the critical factors leading to the failure of clinical cancer treatment such as metastasis and recurrence. However, current strategies suffer from the low stemness-inhibiting efficacy on CSCs by conventional molecular agents and the poor lethal effects against bulk tumor cells. Here we engineer a coordination nanomedicine by 2,5-dihydroxyterephthalic acid (DHT) complexing zinc ions (Zn2+) as a double-effect nanodisrupter of tumor iron (Fe) and redox homeostasis for catalysis-boosted tumor therapy with stemness inhibition. Taking advantage of the much higher binding force of DHT toward Fe3+, this nanomedicine can specifically chelate endogenous Fe3+ into its nanostructure and release Zn2+, and the in situ formed hexacoordinated Fe-DHT conformation is of much enhanced reducibility in order to promote reactive oxygen species (ROS) production in tumors. The nanomedicine-mediated Fe depletion and ROS generation collectively induce CSC differentiation via downregulating the Wnt signaling and inducing forkhead box O3 (FoxO3) activation, respectively. Notably, the combined tumor-selective ROS generation and Zn2+-induced antioxidation dysfunction potently trigger intratumoral oxidative damage leading to both cellular apoptosis and ferroptosis. This nanomedicine, capable of synchronously treating CSCs and bulk tumor cells, has been demonstrated to effectively inhibit the growth, postoperative recurrence and metastasis of orthotopic triple-negative breast tumors in vivo, offering an encouraging candidate of cancer therapeutic agents for treating CSCs-enriched malignancy.
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Affiliation(s)
- Jiajie Chen
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yitong Wang
- Department of Radiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Jian Huang
- Materials Genome Institute, Shanghai University, Shanghai 200444, China
| | - Zhibo Yang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huicong Niu
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 200032, China
| | - Xiaolian Su
- Department of Radiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Jimin Huang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongshi Ma
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yufang Zhu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianlin Shi
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
- Shanghai Frontiers Science Center of Nanocatalytic Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200331, China
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3
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Singh MK, Han S, Kim S, Kang I. Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment. Int J Mol Sci 2024; 25:11185. [PMID: 39456967 PMCID: PMC11508222 DOI: 10.3390/ijms252011185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.
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Affiliation(s)
- Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sungsoo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Kovale L, Singh MK, Kim J, Ha J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int J Mol Sci 2024; 25:8647. [PMID: 39201332 PMCID: PMC11354724 DOI: 10.3390/ijms25168647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
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Affiliation(s)
- Lochana Kovale
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Joungmok Kim
- Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
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5
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Shah S, Mansour HM, Aguilar TM, Lucke-Wold B. Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma. Int J Mol Sci 2024; 25:5694. [PMID: 38891882 PMCID: PMC11171521 DOI: 10.3390/ijms25115694] [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: 04/27/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Hadeel M. Mansour
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Tania M. Aguilar
- College of Medicine at Chicago, University of Illinois, Chicago, IL 60612, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
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6
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Chen ZW, Dong ZB, Xiang HT, Chen SS, Yu WM, Liang C. Helicobacter pylori CagA protein induces gastric cancer stem cell-like properties through the Akt/FOXO3a axis. J Cell Biochem 2024; 125:e30527. [PMID: 38332574 DOI: 10.1002/jcb.30527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/24/2023] [Accepted: 01/04/2024] [Indexed: 02/10/2024]
Abstract
The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.
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Affiliation(s)
- Zheng-Wei Chen
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Zhe-Bin Dong
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Han-Ting Xiang
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Sang-Sang Chen
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Wei-Ming Yu
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Chao Liang
- Department of General Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
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7
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Wang S, Sun Y, Yao L, Xing Y, Yang H, Ma Q. The Role of microRNA-23a-3p in the Progression of Human Aging Process by Targeting FOXO3a. Mol Biotechnol 2024; 66:277-287. [PMID: 37087718 PMCID: PMC10803409 DOI: 10.1007/s12033-023-00746-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 04/02/2023] [Indexed: 04/24/2023]
Abstract
Aging results in deterioration of body functions and, ultimately, death. miRNAs contribute to the regulation of aging. The aim of this study was to explore the contribution of miRNAs to aging and senescence-related changes in gene expression. The expression changes of miRNAs in the blood of people and animal samples collected from different age subjects were examined using Affymetrix miRNA 4.0 microarray and qRT-PCR. MTT assay and flow cytometry were used to examine the effect of miR-23a on cell functions in WI-38 cells. The expression levels of 48 miRNAs, including miR-23a, miR-21, and miR-100, in the blood samples were higher in the middle-aged group than in the young or elderly group. Animal studies further suggested that the expression of miR-23a increased with age. In addition, upregulation of miR-23a dramatically suppressed the cell proliferation and arrested the WI-38 cell cycle in vitro. FOXO3a has been identified as a target gene of miR-23a. MiR-23a downregulated the expression of FOXO3a in WI-38 cells. MiRNAs have different expression levels in different age groups. miR-23a could suppress cell proliferation and arrest the cell cycle in WI-38 cells, which elucidated the mechanism through which miR-23a exerts pivotal role in WI-38 cells by targeting FOXO3a.
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Affiliation(s)
- Shan Wang
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Ying Sun
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Lan Yao
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yunli Xing
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Huayu Yang
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
| | - Qing Ma
- Department of Geriatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
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8
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Tang Z, Zhang Y, Yu Z, Luo Z. Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a. Int J Mol Sci 2023; 24:16611. [PMID: 38068934 PMCID: PMC10705988 DOI: 10.3390/ijms242316611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
| | - Yilan Zhang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhengyi Yu
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
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9
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Santos BF, Grenho I, Martel PJ, Ferreira BI, Link W. FOXO family isoforms. Cell Death Dis 2023; 14:702. [PMID: 37891184 PMCID: PMC10611805 DOI: 10.1038/s41419-023-06177-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/30/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023]
Abstract
FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
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Affiliation(s)
- Bruno F Santos
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Centro Hospitalar Universitário do Algarve (CHUA). Rua Leão Penedo, 8000-386, Faro, Portugal
| | - Inês Grenho
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Paulo J Martel
- Center for Health Technology and Services Research (CINTESIS)@RISE, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Bibiana I Ferreira
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM). Arturo Duperier 4, 28029, Madrid, Spain.
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Tabnak P, Hasanzade Bashkandi A, Ebrahimnezhad M, Soleimani M. Forkhead box transcription factors (FOXOs and FOXM1) in glioma: from molecular mechanisms to therapeutics. Cancer Cell Int 2023; 23:238. [PMID: 37821870 PMCID: PMC10568859 DOI: 10.1186/s12935-023-03090-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/04/2023] [Indexed: 10/13/2023] Open
Abstract
Glioma is the most aggressive and malignant type of primary brain tumor, comprises the majority of central nervous system deaths, and is categorized into different subgroups according to its histological characteristics, including astrocytomas, oligodendrogliomas, glioblastoma multiforme (GBM), and mixed tumors. The forkhead box (FOX) transcription factors comprise a collection of proteins that play various roles in numerous complex molecular cascades and have been discovered to be differentially expressed in distinct glioma subtypes. FOXM1 and FOXOs have been recognized as crucial transcription factors in tumor cells, including glioma cells. Accumulating data indicates that FOXM1 acts as an oncogene in various types of cancers, and a significant part of studies has investigated its function in glioma. Although recent studies considered FOXO subgroups as tumor suppressors, there are pieces of evidence that they may have an oncogenic role. This review will discuss the subtle functions of FOXOs and FOXM1 in gliomas, dissecting their regulatory network with other proteins, microRNAs and their role in glioma progression, including stem cell differentiation and therapy resistance/sensitivity, alongside highlighting recent pharmacological progress for modulating their expression.
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Affiliation(s)
- Peyman Tabnak
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Mohammad Ebrahimnezhad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdieh Soleimani
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Zaarour RF, Ribeiro M, Azzarone B, Kapoor S, Chouaib S. Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance. Front Oncol 2023; 13:1222575. [PMID: 37886168 PMCID: PMC10598765 DOI: 10.3389/fonc.2023.1222575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
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Affiliation(s)
- RF. Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - M. Ribeiro
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - B. Azzarone
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - S. Kapoor
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - S. Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, Villejuif, France
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12
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Flores D, Lopez A, Udawant S, Gunn B, Keniry M. The FOXO1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal-like breast cancer cells. FEBS Open Bio 2023; 13:352-362. [PMID: 36602390 PMCID: PMC9900086 DOI: 10.1002/2211-5463.13547] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/06/2023] Open
Abstract
Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor-prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell-permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor-prognosis cancers.
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Affiliation(s)
- David Flores
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Alma Lopez
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Shreya Udawant
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Bonnie Gunn
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Megan Keniry
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
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13
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Ervin EH, French R, Chang CH, Pauklin S. Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer. Semin Cancer Biol 2022; 87:48-83. [PMID: 36347438 DOI: 10.1016/j.semcancer.2022.11.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/22/2022] [Accepted: 11/03/2022] [Indexed: 11/07/2022]
Abstract
Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
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Affiliation(s)
- Egle-Helene Ervin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Rhiannon French
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
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14
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Ohno M, Kitanaka C, Miyakita Y, Tanaka S, Sonoda Y, Mishima K, Ishikawa E, Takahashi M, Yanagisawa S, Ohashi K, Nagane M, Narita Y. Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies. Cancers (Basel) 2022; 14:cancers14174222. [PMID: 36077758 PMCID: PMC9454846 DOI: 10.3390/cancers14174222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.
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Affiliation(s)
- Makoto Ohno
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Chifumi Kitanaka
- Department of Molecular Cancer Science, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Yasuji Miyakita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shota Tanaka
- Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yukihiko Sonoda
- Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Kazuhiko Mishima
- Department of Neuro-Oncology/Neurosurgery, International Medical Center, Saitama Medical University, Hidaka 350-1298, Japan
| | - Eiichi Ishikawa
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba 350-8576, Japan
| | - Masamichi Takahashi
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shunsuke Yanagisawa
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Ken Ohashi
- Department of General Internal Medicine, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Motoo Nagane
- Department of Neurosurgery, Kyorin University Faculty of Medicine, Mitaka 181-8611, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
- Correspondence: ; Tel.: +81-3-3542-2511
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15
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Shafi O, Siddiqui G. Tracing the origins of glioblastoma by investigating the role of gliogenic and related neurogenic genes/signaling pathways in GBM development: a systematic review. World J Surg Oncol 2022; 20:146. [PMID: 35538578 PMCID: PMC9087910 DOI: 10.1186/s12957-022-02602-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/15/2022] [Indexed: 02/16/2023] Open
Abstract
Background Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM, and for this purpose, it focuses primarily on developmental gliogenic processes. It also focuses on the impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons. Methods Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, and astrocytogenic genes. Results The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate-specific genes to keep the cells differentiated in their specific cell types such as p300, BMP, HOPX, and NRSF/REST. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, and hey1. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300, and then GFAP, leading to upregulation of nestin, SHH, NF-κB, and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. Conclusion Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, and TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, and ASCL1. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR, and others.
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Affiliation(s)
- Ovais Shafi
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan.
| | - Ghazia Siddiqui
- Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan
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16
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Audesse AJ, Karashchuk G, Gardell ZA, Lakis NS, Maybury-Lewis SY, Brown AK, Leeman DS, Teo YV, Neretti N, Anthony DC, Brodsky AS, Webb AE. FOXO3 regulates a common genomic program in aging and glioblastoma stem cells. AGING AND CANCER 2021; 2:137-159. [PMID: 36303712 PMCID: PMC9601604 DOI: 10.1002/aac2.12043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 11/14/2021] [Indexed: 01/14/2023]
Abstract
Background Glioblastoma (GBM) is an aggressive, age-associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM-derived GSCs. Using RNA-seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3-regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions This work identifies a FOXO-associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.
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Affiliation(s)
- Amanda J. Audesse
- Neuroscience Graduate Program, Brown University, Providence, Rhode Island, USA
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Galina Karashchuk
- Department of Pathology and Laboratory Medicine, Lifespan Academic Medical Center and Warren Alpert Medical School at Brown University, Providence, Rhode Island, USA
| | - Zachary A. Gardell
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
| | - Nelli S. Lakis
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sun Y. Maybury-Lewis
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
- Molecular Biology, Cell Biology, and Biochemistry Graduate Program, Brown University, Providence, Rhode Island, USA
| | - Abigail K. Brown
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
- Molecular Biology, Cell Biology, and Biochemistry Graduate Program, Brown University, Providence, Rhode Island, USA
| | - Dena S. Leeman
- Department of Discovery Immunology, Genentech, Inc., South San Francisco, California, USA
| | - Yee Voan Teo
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
- Molecular Biology, Cell Biology, and Biochemistry Graduate Program, Brown University, Providence, Rhode Island, USA
| | - Nicola Neretti
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
- Center on the Biology of Aging, Brown University, Providence, Rhode Island, USA
| | - Douglas C. Anthony
- Department of Pathology and Laboratory Medicine, Lifespan Academic Medical Center and Warren Alpert Medical School at Brown University, Providence, Rhode Island, USA
- Department of Neurology, Brown University, Providence, Rhode Island, USA
| | - Alexander S. Brodsky
- Department of Pathology and Laboratory Medicine, Lifespan Academic Medical Center and Warren Alpert Medical School at Brown University, Providence, Rhode Island, USA
| | - Ashley E. Webb
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA
- Center on the Biology of Aging, Brown University, Providence, Rhode Island, USA
- Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA
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17
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Yang S, Pang L, Dai W, Wu S, Ren T, Duan Y, Zheng Y, Bi S, Zhang X, Kong J. Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review). Front Oncol 2021; 11:667730. [PMID: 34123834 PMCID: PMC8190381 DOI: 10.3389/fonc.2021.667730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/28/2021] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.
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Affiliation(s)
- Shaojie Yang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Liwei Pang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wanlin Dai
- Innovation Institute of China Medical University, Shenyang, China
| | - Shuodong Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tengqi Ren
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yunlong Duan
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuting Zheng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyuan Bi
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaolin Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing Kong
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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18
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Alves ALV, Gomes INF, Carloni AC, Rosa MN, da Silva LS, Evangelista AF, Reis RM, Silva VAO. Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. Stem Cell Res Ther 2021; 12:206. [PMID: 33762015 PMCID: PMC7992331 DOI: 10.1186/s13287-021-02231-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15–18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.
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Affiliation(s)
- Ana Laura V Alves
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Izabela N F Gomes
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Adriana C Carloni
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Marcela N Rosa
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Luciane S da Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Adriane F Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's PT Government Associate Laboratory, 4806-909, Braga, Portugal
| | - Viviane Aline O Silva
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, CEP 14784 400, Barretos, São Paulo, Brazil.
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19
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Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:17-43. [PMID: 34337348 PMCID: PMC8319838 DOI: 10.20517/cdr.2020.79] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.
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Affiliation(s)
- Neha Singh
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Alexandra Miner
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Lauren Hennis
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Sandeep Mittal
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA.,Carilion Clinic - Neurosurgery, Roanoke, VA 24014, USA
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20
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Castelli V, Giordano A, Benedetti E, Giansanti F, Quintiliani M, Cimini A, d’Angelo M. The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death. Cancers (Basel) 2021; 13:328. [PMID: 33477367 PMCID: PMC7830655 DOI: 10.3390/cancers13020328] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial-mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation.
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Affiliation(s)
- Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Antonio Giordano
- Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy;
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Francesco Giansanti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Massimiliano Quintiliani
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
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21
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Farhan M, Silva M, Li S, Yan F, Fang J, Peng T, Hu J, Tsao M, Little P, Zheng W. The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development. Med Res Rev 2020; 40:2089-2113. [PMID: 32474970 PMCID: PMC7586888 DOI: 10.1002/med.21695] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 04/21/2020] [Accepted: 05/16/2020] [Indexed: 12/17/2022]
Abstract
Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.
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Affiliation(s)
- Mohd Farhan
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Marta Silva
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Shuai Li
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Fengxia Yan
- Department of MedicineJinan UniversityGuangzhouChina
| | - Jiankang Fang
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Tangming Peng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Jim Hu
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Ming‐Sound Tsao
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Peter Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of QueenslandWoolloongabbaQueenslandAustralia
| | - Wenhua Zheng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
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22
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Mandhair HK, Arambasic M, Novak U, Radpour R. Molecular modulation of autophagy: New venture to target resistant cancer stem cells. World J Stem Cells 2020; 12:303-322. [PMID: 32547680 PMCID: PMC7280868 DOI: 10.4252/wjsc.v12.i5.303] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a highly regulated catabolic process in which superfluous, damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions. Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers. For instance, autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses, by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics. Autophagy has been implicated in a cross talk with apoptosis. Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients. In this review, we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Miroslav Arambasic
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland.
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Yang Y, Wang QQ, Bozinov O, Xu RX, Sun YL, Wang SS. GSK‑3 inhibitor CHIR99021 enriches glioma stem‑like cells. Oncol Rep 2020; 43:1479-1490. [PMID: 32323804 PMCID: PMC7108089 DOI: 10.3892/or.2020.7525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/14/2020] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain cancer. The disease is essentially incurable, with glioblastomas characterized by resistance to both chemotherapy and radiotherapy, as well as by rapid tumor progression, all of which are mainly ascribed to glioma stem-like cells (GSLCs). In the present study, an improved model that is more similar to clinical GBM was constructed. Twenty clinical glioma samples were collected to obtain primary low-grade tumor cells. The cells were either maintained in serum-free medium as primary glioma-based cells (PGBCs) or cultured in the same medium with CHIR99021 as GSLCs. Then, the molecular and ultrastructural differences between the two cell groups were determined. Furthermore, the proliferation and migration of the GSLCs were examined and the potential mechanisms were investigated. Finally, temozolomide resistance in vitro and in the mouse model was assessed to study the properties of the induced GSLCs. The primary low-grade tumor cells extracted from surgical samples were enriched with GSLC properties, with high expression levels of CD133 and Nestin in 100 nM CHIR99021. The GSLCs exhibited high proliferation and migration. Furthermore, the expression of the PI3K/AKT signaling pathway and that of related genes and proteins were significantly enhanced by CHIR99021. The animal study also revealed high levels of STAT3, mTOR, NF-κB, and VEGF in the GSLC-transplanted mice. CHIR99021 could stably enhance GSLC properties in patient-derived glioma samples. It may provide a useful model for further study, helping to understand the pathogenesis of therapeutic resistance and to screen drug candidates.
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Affiliation(s)
- Yang Yang
- Department of Neurosurgery, University Hospital of Zurich, University of Zurich, CH‑8091 Zurich, Switzerland
| | - Qin-Qin Wang
- Neurosurgical Institute, The Seventh Medical Center of PLA Army General Hospital, Beijing 100700, P.R. China
| | - Oliver Bozinov
- Department of Neurosurgery, University Hospital of Zurich, University of Zurich, CH‑8091 Zurich, Switzerland
| | - Ru-Xiang Xu
- Neurosurgical Institute, The Seventh Medical Center of PLA Army General Hospital, Beijing 100700, P.R. China
| | - Yi-Lin Sun
- Neurosurgical Institute, The Seventh Medical Center of PLA Army General Hospital, Beijing 100700, P.R. China
| | - Shan-Shan Wang
- Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, P.R. China
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The PI3K pathway impacts stem gene expression in a set of glioblastoma cell lines. J Cancer Res Clin Oncol 2020; 146:593-604. [PMID: 32030510 DOI: 10.1007/s00432-020-03133-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/16/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The PI3K pathway controls diverse cellular processes including growth, survival, metabolism, and apoptosis. Nuclear FOXO factors were observed in cancers that harbor constitutively active PI3K pathway output and stem signatures. FOXO1 and FOXO3 were previously published to induce stem genes such as OCT4 in embryonic stem cells. Here, we investigated FOXO-driven stem gene expression in U87MG glioblastoma cells. METHODS PI3K-activated cancer cell lines were investigated for changes in gene expression, signal transduction, and clonogenicity under conditions with FOXO3 disruption or exogenous expression. The impact of PI3K pathway inhibition on stem gene expression was examined in a set of glioblastoma cell lines. RESULTS We found that CRISPR-Cas9-mediated FOXO3 disruption in U87MG cells caused decreased OCT4 and SOX2 gene expression, STAT3 phosphorylation on tyrosine 705 and clonogenicity. FOXO3 over expression led to increased OCT4 in numerous glioblastoma cancer cell lines. Strikingly, treatment of glioblastoma cells with NVP-BEZ235 (a dual inhibitor of PI3K and mTOR), which activates FOXO factors, led to robust increases OCT4 gene expression. Direct FOXO factor recruitment to the OCT4 promoter was detected by chromatin immunoprecipitation analyses using U87MG extracts. DISCUSSION We show for the first time that FOXO transcription factors promote stem gene expression glioblastoma cells. Treatment with PI3K inhibitor NVP-BEZ235 led to dramatic increases in stem genes in a set of glioblastoma cell lines. CONCLUSION Given that, PI3K inhibitors are actively investigated as targeted cancer therapies, the FOXO-mediated induction of stem genes observed in this study highlights a potential hazard to PI3K inhibition. Understanding the molecular underpinnings of stem signatures in cancer will allow refinements to therapeutic strategies. Targeting FOXO factors to reduce stem cell characteristics in concert with PI3K inhibition may prove therapeutically efficacious.
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25
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Gan Y, Ye F, He XX. The role of YWHAZ in cancer: A maze of opportunities and challenges. J Cancer 2020; 11:2252-2264. [PMID: 32127952 PMCID: PMC7052942 DOI: 10.7150/jca.41316] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 11/30/2019] [Indexed: 12/21/2022] Open
Abstract
YWHAZ (also named 14-3-3ζ) is a central hub protein for many signal transduction pathways and plays a significant role in tumor progression. Accumulating evidences have demonstrated that YWHAZ is frequently up-regulated in multiple types of cancers and acts as an oncogene in a wide range of cell activities including cell growth, cell cycle, apoptosis, migration, and invasion. Moreover, YWHAZ was reported to be regulated by microRNAs (miRNAs) or long non-coding RNAs and exerted its malignant functions by targeting downstream molecules like protein kinase, apoptosis proteins, and metastasis-related molecules. Additionally, YWHAZ may be a potential biomarker of diagnosis, prognosis and chemoresistance in several cancers. Targeting YWHAZ by siRNA, shRNA or miRNA was reported to have great help in suppressing malignant properties of cancer cells. In this review, we perform literature and bioinformatics analysis to reveal the oncogenic role and molecular mechanism of YWHAZ in cancer, and discuss the potential clinical applications of YWHAZ concerning diagnosis, prognosis, and therapy in malignant tumors.
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Affiliation(s)
- Yun Gan
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Ye
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Xing He
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mazurek M, Litak J, Kamieniak P, Kulesza B, Jonak K, Baj J, Grochowski C. Metformin as Potential Therapy for High-Grade Glioma. Cancers (Basel) 2020; 12:E210. [PMID: 31952173 PMCID: PMC7016983 DOI: 10.3390/cancers12010210] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.
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Affiliation(s)
- Marek Mazurek
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Jakub Litak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
- Department of Immunology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Piotr Kamieniak
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Bartłomiej Kulesza
- Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland; (M.M.); (J.L.); (P.K.); (B.K.)
| | - Katarzyna Jonak
- Department of Foregin Languages, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Cezary Grochowski
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
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27
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Koguchi M, Nakahara Y, Ito H, Wakamiya T, Yoshioka F, Ogata A, Inoue K, Masuoka J, Izumi H, Abe T. BMP4 induces asymmetric cell division in human glioma stem-like cells. Oncol Lett 2019; 19:1247-1254. [PMID: 31966054 PMCID: PMC6956386 DOI: 10.3892/ol.2019.11231] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/25/2019] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is a malignant tumor with a high recurrence rate and has very poor prognosis in humans. The median survival is still <2 years. Therefore, a new treatment strategy should be established. Recently, this cancer has been thought to be heterogeneous, consisting of cancer stem cells (CSCs) that are self-renewable, multipotent, and treatment resistant. So various strategies targeting glioma stem-like cells (GSCs) have been investigated. This study focused on strategies targeting GSCs through the induction of differentiation using bone morphogenetic protein 4 (BMP4). The expression of CD133, a cancer stem cell marker, under BMP4 treatment in GSCs was examined using flow cytometry, western blotting, and quantitative PCR. Immunofluorescent staining of GSCs was also performed to examine the type of cell division: asymmetric cell division (ACD) or symmetric cell division (SCD). We obtained the following results. The BMP4 treatment caused downregulation of CD133 expression. Moreover, it induced ACD in GSCs. While the ACD ratio was 23% without BMP4 treatment, it was 38% with BMP4 treatment (P=0.004). Furthermore, the tumor sphere assay demonstrated that BMP4 suppresses self-renewal ability. In conclusion, these findings may provide a new perspective on how BMP4 treatment reduces the tumorigenicity of GSCs.
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Affiliation(s)
- Motofumi Koguchi
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Yukiko Nakahara
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Hiroshi Ito
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Tomihiro Wakamiya
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Fumitaka Yoshioka
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Atsushi Ogata
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kohei Inoue
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Jun Masuoka
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Hideki Izumi
- Laboratory of Molecular Medicine, Life Sciences Institute, Saga Medical Center KOSEIKAN, Saga 840-8571, Japan
| | - Tatsuya Abe
- Department of Neurosurgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan
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Abstract
Cancer stem cells (CSC) are a subpopulation of tumor cells that have superior capacities of self-renewal, metastatic dissemination, and chemoresistance. These characteristics resemble, to some extent, the outcome of certain biological processes, including epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. Indeed, it has been shown that the stimuli that induce these processes and CSC are overlapping, and CSC and tumor cells that underwent EMT or autophagy are much alike. However, as the cross talk between CSC, EMT, autophagy, and cellular stress is further explored, these processes are also found to have an opposing role in CSC, depending on the condition and status of cells. This contextual effect is likely due to overwhelming reliance on CSC markers for their identification, and/or discrepancies in recognition of CSC as a particular cell population or cellular state. In this review, we summarize how EMT, autophagy, and cellular stress response are tied or unwound with CSC. We also discuss the current view of CSC theory evolved from the emphasis of heterogenicity and plasticity of CSC.
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Affiliation(s)
- Kai-Feng Hung
- Department of Medical Research, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Ting Yang
- Department of Medical Research, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shou-Yen Kao
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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29
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Libby CJ, McConathy J, Darley-Usmar V, Hjelmeland AB. The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology. Cancer Res 2019; 80:5-16. [PMID: 31575548 DOI: 10.1158/0008-5472.can-19-1169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 08/04/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023]
Abstract
Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.
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Affiliation(s)
- Catherine J Libby
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jonathan McConathy
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor Darley-Usmar
- Mitochondrial Medicine Laboratory, Center for Free Radical Biology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
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30
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Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ 2019; 27:966-983. [PMID: 31296961 PMCID: PMC7206060 DOI: 10.1038/s41418-019-0389-3] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 06/15/2019] [Accepted: 06/24/2019] [Indexed: 12/20/2022] Open
Abstract
Breast cancer stem cells (BCSCs) are tumor initiating cells that can self-renew and are highly tumorigenic and chemoresistant. Therefore, the identification of factors critical for BCSC function is vital for the development of therapies. Here, we report that DNMT1-mediated FOXO3a promoter hypermethylation leads to downregulation of FOXO3a expression in breast cancer. FOXO3a is functionally related to the inhibition of FOXM1/SOX2 signaling and to the consequent suppression of BCSCs properties and tumorigenicity. Moreover, we found that SOX2 directly transactivates DNMT1 expression and thereby alters the methylation landscape, which in turn feedback inhibits FOXO3a expression. Inhibition of DNMT activity suppressed tumor growth via regulation of FOXO3a/FOXM1/SOX2 signaling in breast cancer. Clinically, we observed a significant inverse correlation between FOXO3a and FOXM1/SOX2/DNMT1 expression levels, and loss of FOXO3a expression or increased expression of FOXM1, SOX2, and DNMT1 predicted poor prognosis in breast cancer. Collectively, our findings suggest an important role of the DNMT1/FOXO3a/FOXM1/SOX2 pathway in regulating BCSCs properties, suggesting potential therapeutic targets for breast cancer.
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31
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He J, Yang Z, Wu Z, Wang L, Xu S, Zou Q, Yuan Y, Li D. Expression of FOXP1 and FOXO3a in extrahepatic cholangiocarcinoma and the implications in clinicopathological significance and prognosis. Onco Targets Ther 2019; 12:2955-2965. [PMID: 31114239 PMCID: PMC6489656 DOI: 10.2147/ott.s197001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 03/23/2019] [Indexed: 12/14/2022] Open
Abstract
Aims: Extrahepatic cholangiocarcinoma (EHCC) is a highly malignant tumor with poor prognosis and intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of FOXP1 and FOXO3a expression in EHCC. Methods: We assayed FOXP1 and FOXO3a expressions in 100 EHCC, 30 peritumoral tissues, 10 adenoma and 15 normal biliary tract tissues using EnVision immunohistochemistry. Results: The positive rates of FOXP1 and FOXO3a proteins were significantly lower in EHCC tumors than in peritumoral tissues, adenoma, and normal bile tract tissues (P<0.05 or P<0.01). Adenoma and pericancerous tissues with negative FOXP1 and/or FOXO3a protein expressions exhibited atypical hyperplasia. The positive correlation was established between the expression of FOXP1 and FOXO3a in EHCC (P<0.01). The positive rates of FOXP1 and FOXO3a expression were significantly higher in cases with well differentiation, no metastasis in lymph node, no invasion to surrounding tissues and organs, TNM I + II stage and radical resection (p<0.05 or p<0.01). Kaplan-Meier survival analysis showed that EHCC patients with positive FOXP1 and FOXO3a expression survived significantly higher than patients with negative FOXP1 and FOXO3a expression, respectively (P<0.001). Cox multivariate analysis revealed that negative FOXP1 or FOXO3a expressions were independent poor prognostic factors in EHCC patients. The AUCs for FOXP1 and FOXO3a were 0.676 (95% CI: 0.589–0.763, P<0.001) and 0.652 (95% CI: 0.563–741, P=0.002), respectively. Conclusion: The present study indicates that negative FOXP1 and FOXO3a expressions are closely associated with the pathogenesis, clinical, pathological and biological behaviors, and poor prognosis in EHCC.
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Affiliation(s)
- Jun He
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhulin Yang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhengchun Wu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Lingxiang Wang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Shu Xu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Daiqiang Li
- Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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The tumor suppressor FOXO3a mediates the response to EGFR inhibition in glioblastoma cells. Cell Oncol (Dordr) 2019; 42:521-536. [PMID: 30980364 DOI: 10.1007/s13402-019-00443-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2019] [Indexed: 10/27/2022] Open
Abstract
PURPOSE Although EGFR activation is a hallmark of glioblastoma (GBM), anti-EGFR therapy has so far not yielded the desired effects. Targeting PI3K/Akt has been proposed as a strategy to increase the cellular sensitivity to EGFR inhibitors. Here we evaluated the contribution of FOXO3a, a key Akt target, in the response of GBM cells to EGFR inhibition. METHODS FOXO3a activation was assessed by immunofluorescence and gene reporter assays, and by evaluating target gene expression using Western blotting and qRT-PCR. Cellular effects were evaluated using cell viability and apoptosis assays, i.e., Annexin V/PI staining and caspase 3/7 activity measurements. Drug synergism was evaluated by performing isobolographic analyses. Gene silencing experiments were performed using stable shRNA transfections. RESULTS We found that EGFR inhibition in GBM cells led to FOXO3a activation and to transcriptional modulation of its key targets, including repression of the oncogene FOXM1. In addition, we found that specific FOXO3a activation recapitulated the molecular effects of EGFR inhibition, and that the FOXO3a activator trifluoperazine, a FDA-approved antipsychotic agent, reduced GBM cell growth. Subsequent isobolographic analyses of combination experiments indicated that trifluoperazine and erlotinib cooperated synergistically and that their concomitant treatment induced a robust activation of FOXO3a, leading to apoptosis in GBM cells. Using gene silencing, we found that FOXO3a is essential for the response of GBM cells to EGFR inhibition. CONCLUSIONS Our data indicate that FOXO3a activation is a crucial event in the response of GBM cells to EGFR inhibition, suggesting that FOXO3a may serve as an actionable therapeutic target that can be modulated using FDA-approved drugs.
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Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F. Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ 2019; 26:690-702. [PMID: 30728463 PMCID: PMC6460398 DOI: 10.1038/s41418-019-0292-y] [Citation(s) in RCA: 282] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 02/07/2023] Open
Abstract
Autophagy and mitophagy act in cancer as bimodal processes, whose differential functions strictly depend on cancer ontogenesis, progression, and type. For instance, they can act to promote cancer progression by helping cancer cells survive stress or, instead, when mutated or abnormal, to induce carcinogenesis by influencing cell signaling or promoting intracellular toxicity. For this reason, the study of autophagy in cancer is the main focus of many researchers and several clinical trials are already ongoing to manipulate autophagy and by this way determine the outcome of disease therapy. Since the establishment of the cancer stem cell (CSC) theory and the discovery of CSCs in individual cancer types, autophagy and mitophagy have been proposed as key mechanisms in their homeostasis, dismissal or spread, even though we still miss a comprehensive view of how and by which regulatory molecules these two processes drive cell fate. In this review, we will dive into the deep water of autophagy, mitophagy, and CSCs and offer novel viewpoints on possible therapeutic strategies, based on the modulation of these degradative systems.
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Affiliation(s)
- Francesca Nazio
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
| | - Matteo Bordi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy
| | - Valentina Cianfanelli
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Franco Locatelli
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Gynecology/Obstetrics and Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Francesco Cecconi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy.
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy.
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
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34
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Chen AS, Read RD. Drosophila melanogaster as a Model System for Human Glioblastomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1167:207-224. [PMID: 31520357 DOI: 10.1007/978-3-030-23629-8_12] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Genomic amplifications, activating mutations, and overexpression of receptor tyrosine kinases (RTKs) such as EGFR, and genes in core RTK signaling transduction pathways such as PI3K are common in GBM. However, efforts to target these pathways have been largely unsuccessful in the clinic, and the median survival of GBM patients remains poor at 14-15 months. Therefore, to improve patient outcomes, there must be a concerted effort to elucidate the underlying biology involved in GBM tumorigenesis. Drosophila melanogaster has been a highly effective model for furthering our understanding of GBM tumorigenesis due to a number of experimental advantages it has over traditional mouse models. For example, there exists extensive cellular and genetic homology between humans and Drosophila, and 75% of genes associated with human disease have functional fly orthologs. To take advantage of these traits, we developed a Drosophila GBM model with constitutively active variants of EGFR and PI3K that effectively recapitulated key aspects of GBM disease. Researchers have utilized this model in forward genetic screens and have expanded on its functionality to make a number of important discoveries regarding requirements for key components in GBM tumorigenesis, including genes and pathways involved in extracellular matrix signaling, glycolytic metabolism, invasion/migration, stem cell fate and differentiation, and asymmetric cell division. Drosophila will continue to reveal novel biological pathways and mechanisms involved in gliomagenesis, and this knowledge may contribute to the development of effective treatment strategies to improve patient outcomes.
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Affiliation(s)
- Alexander S Chen
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Renee D Read
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. .,Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. .,Winship Cancer Center, Emory University School of Medicine, Atlanta, GA, USA.
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35
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Chen X, Dong D, Pan C, Xu C, Sun Y, Geng Y, Kong L, Xiao X, Zhao Z, Zhou W, Huang L, Song Y, Zhang L. Identification of Grade-associated MicroRNAs in Brainstem Gliomas Based on Microarray Data. J Cancer 2018; 9:4463-4476. [PMID: 30519352 PMCID: PMC6277643 DOI: 10.7150/jca.26417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 08/01/2018] [Indexed: 12/19/2022] Open
Abstract
Gliomas arising in the brainstem are rare tumours that are difficult to surgically resect, and the microRNAs (miRNAs) and signalling pathways associated with brainstem gliomas (BSGs) are largely unknown. To identify grade-associated miRNAs in BSGs, a microarray analysis of 10 low-grade and 15 high-grade BSGs was performed in this study. Differentially expressed miRNAs (DE-miRNAs) were identified, and the functional DE-miRNAs were selected. The potential target genes and enriched pathways were analysed, and a target gene-associated protein-protein interaction (PPI) network was generated. Grade-associated functional DE-miRNAs were confirmed by real-time quantitative PCR. First, 28 functional DE-miRNAs, including 13 upregulated miRNAs and 15 downregulated miRNAs, were identified. Second, 2546 target genes that were involved in BSG-related pathways, such as signalling pathways regulating the pluripotency of stem cells, the AMPK signalling pathway, the HIF-1 signalling pathway, the PI3K-Akt signalling pathway, the Wnt signalling pathway and the Hippo signalling pathway, were screened. Third, PHLPP2 and VEGFA were identified as hub genes in the PPI network. Last, we found that hsa-miR-34a-5p inhibits BSG cell invasion in vitro. In summary, using integrated bioinformatics analysis, we have identified the potential target genes and pathways of grade-associated functional DE-miRNAs in BSGs, which could improve the accuracy of prognostic evaluation. Furthermore, these hub genes and pathways could be therapeutic targets for the treatment of BSGs.
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Affiliation(s)
- Xin Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Dezuo Dong
- Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Changcun Pan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Cheng Xu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Yu Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Yibo Geng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Lu Kong
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Xiong Xiao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
| | - Zitong Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wei Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lijie Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yongmei Song
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liwei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantanxili 6, Dongcheng District, Beijing, 100050, China
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36
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Angelucci C, D'Alessio A, Lama G, Binda E, Mangiola A, Vescovi AL, Proietti G, Masuelli L, Bei R, Fazi B, Ciafrè SA, Sica G. Cancer stem cells from peritumoral tissue of glioblastoma multiforme: the possible missing link between tumor development and progression. Oncotarget 2018; 9:28116-28130. [PMID: 29963265 PMCID: PMC6021333 DOI: 10.18632/oncotarget.25565] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 05/19/2018] [Indexed: 12/15/2022] Open
Abstract
In glioblastoma multiforme (GBM), cancer stem cells (CSCs) are thought to be responsible for gliomagenesis, resistance to treatment and recurrence. Unfortunately, the prognosis for GBM remains poor and recurrence frequently occurs in the peritumoral tissue within 2 cm from the tumor edge. In this area, a population of CSCs has been demonstrated which may recapitulate the tumor after surgical resection. In the present study, we aimed to characterize CSCs derived from both peritumoral tissue (PCSCs) and GBM (GCSCs) in order to deepen their significance in GBM development and progression. The stemness of PCSC/GCSC pairs obtained from four human GBM surgical specimens was investigated by comparing the expression of specific stem cell markers such as Nestin, Musashi-1 and SOX2. In addition, the growth rate, the ultrastructural features and the expression of other molecules such as c-Met, pMet and MAP kinases, involved in cell migration/invasion, maintenance of tumor stemness and/or resistance to treatments were evaluated. Since it has been recently demonstrated the involvement of the long non-coding RNAs (lncRNAs) in the progression of gliomas, the expression of H19 lncRNA, as well as of one of its two mature products miR-675-5p was evaluated in neurospheres. Our results show significant differences between GCSCs and PCSCs in terms of proliferation, ultrastructural peculiarities and, at a lower extent, stemness profile. These differences might be important in view of their potential role as a therapeutic target.
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Affiliation(s)
- Cristiana Angelucci
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Alessio D'Alessio
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Gina Lama
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Elena Binda
- Cancer Stem Cells Unit, IRCSS Casa Sollievo della Sofferenza, ISBReMIT-Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Opera di San Pio da Pietrelcina, S. Giovanni Rotondo, Foggia, Italy
| | - Annunziato Mangiola
- Istituto di Neurochirurgia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Angelo L Vescovi
- Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy.,IRCSS Casa Sollievo della Sofferenza, ISBReMIT-Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Opera di San Pio da Pietrelcina, S. Giovanni Rotondo, Foggia, Italy.,Hyperstem SA, Lugano, Switzerland
| | - Gabriella Proietti
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Barbara Fazi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Silvia Anna Ciafrè
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Gigliola Sica
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
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37
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Firat E, Niedermann G. FoxO proteins or loss of functional p53 maintain stemness of glioblastoma stem cells and survival after ionizing radiation plus PI3K/mTOR inhibition. Oncotarget 2018; 7:54883-54896. [PMID: 27448972 PMCID: PMC5342388 DOI: 10.18632/oncotarget.10702] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/12/2016] [Indexed: 01/08/2023] Open
Abstract
Dual PI3K/mTOR inhibitors do not effectively radiosensitize glioblastoma multiforme stem cells (GBM-SCs), but p53-proficient GBM-SCs are more responsive than p53-deficient ones. Here, we found that p53-proficient, but not p53-deficient, GBM-SCs lost stemness and differentiated after γ-irradiation combined with PI3K/mTOR inhibition; expression of FoxO proteins was also lost. FoxO overexpression inhibited the loss of stem cell markers under these conditions. Combined, but not single, FoxO1/3 deletion or pharmacological inhibition of FoxO transcriptional activity strongly reduced stem and progenitor marker expression, particularly that of Sox2. Binding of FoxO1 and FoxO3 to the sox2 regulatory regions was also found. However, combined FoxO1/3 knockdown strongly reduced self-renewal and post-treatment survival only in p53-proficient GBM-SCs. This suggests that FoxO1 and FoxO3 are crucial for functional stemness and post-treatment survival mainly in p53-proficient but not in p53-deficient GBM-SCs, and that these functions can be maintained through the loss of DNA damage-responsive p53 instead.
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Affiliation(s)
- Elke Firat
- Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany
| | - Gabriele Niedermann
- Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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van Doeselaar S, Burgering BMT. FOXOs Maintaining the Equilibrium for Better or for Worse. Curr Top Dev Biol 2018; 127:49-103. [PMID: 29433740 DOI: 10.1016/bs.ctdb.2017.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A paradigm shift is emerging within the FOXO field and accumulating evidence indicates that we need to reappreciate the role of FOXOs, at least in cancer development. Here, we discuss the possibility that FOXOs are both tumor suppressors as well as promoters of tumor progression. This is mostly dependent on the biological context. Critical to this dichotomous role is the notion that FOXOs are central in preserving cellular homeostasis in redox control, genomic stability, and protein turnover. From this perspective, a paradoxical role in both suppressing and enhancing tumor progression can be reconciled. As many small molecules targeting the PI3K pathway are developed by big pharmaceutical companies and/or are in clinical trial, we will discuss what the consequences may be for the context-dependent role of FOXOs in tumor development in treatment options based on active PI3K signaling in tumors.
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Affiliation(s)
- Sabina van Doeselaar
- Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Boudewijn M T Burgering
- Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
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39
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Park SY, Piao Y, Thomas C, Fuller GN, de Groot JF. Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma. Oncotarget 2018; 7:26793-805. [PMID: 27050366 PMCID: PMC5042015 DOI: 10.18632/oncotarget.8471] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 03/10/2016] [Indexed: 01/09/2023] Open
Abstract
Cdc2-like kinase 2 (CLK2) is known as a regulator of RNA splicing that ultimately controls multiple physiological processes. However, the function of CLK2 in glioblastoma progression has not been described. Reverse-phase protein array (RPPA) was performed to identify proteins differentially expressed in CLK2 knockdown cells compared to controls. The RPPA results indicated that CLK2 knockdown influenced the expression of survival-, proliferation-, and cell cycle-related proteins in GSCs. Thus, knockdown of CLK2 expression arrested the cell cycle at the G1 and S checkpoints in multiple GSC lines. Depletion of CLK2 regulated the dephosphorylation of AKT and decreased phosphorylation of Forkhead box O3a (FOXO3a), which not only translocated to the nucleus but also increased p27 expression. In two glioblastoma xenograft models, the survival duration of mice with CLK2-knockdown GSCs was significantly longer than mice with control tumors. Additionally, tumor volumes were significantly smaller in CLK2-knockdown mice than in controls. Knockdown of CLK2 expression reduced the phosphorylation of FOXO3a and decreased Ki-67 in vivo. Finally, high expression of CLK2 protien was significantly associated with worse patient survival. These findings suggest that CLK2 plays a critical role in controlling the cell cycle and survival of glioblastoma via FOXO3a/p27.
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Affiliation(s)
- Soon Young Park
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yuji Piao
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Craig Thomas
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gregory N Fuller
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John F de Groot
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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40
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Pain M, Wang H, Lee E, Strahl M, Hamou W, Sebra R, Zhu J, Yong RL. Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma. Oncotarget 2017; 9:2603-2621. [PMID: 29416795 PMCID: PMC5788663 DOI: 10.18632/oncotarget.23517] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 12/11/2017] [Indexed: 11/25/2022] Open
Abstract
Background Gliosarcoma is a rare variant of glioblastoma (GBM) that exhibits frequent mutations in TP53 and can develop in a secondary fashion after chemoradiation of a primary GBM. Whether temozolomide (TMZ)-induced mutagenesis of the TP53 DNA-binding domain (DBD) can drive the pathogenesis of gliosarcoma is unclear. Methods We identified a case of a primary GBM that rapidly progressed into secondary gliosarcoma shortly after chemoradiation was initiated. Bulk tumor was collected and gliomasphere cultures derived from both the pre- and post-treatment tumors. We performed targeted DNA sequencing and transcriptome analyses of the specimens to understand their phylogenetic relationship and identify differentially expressed gene pathways. Gliomaspheres from the primary GBM were treated with TMZ and then analyzed to compare patterns of mutagenesis in vivo and ex vivo. Results The pre- and post-treatment tumors shared EGFR, CDKN2A, and PTEN mutations, but only the secondary gliosarcoma exhibited TP53 DBD missense mutations. Two mutations, R110C, and R175H, were identified, each in distinct clones. Both were base transitions characteristic of TMZ mutagenesis. Gene expression analysis identified increased JAK-STAT signaling in the gliosarcoma, together with reduced expression of microRNAs known to regulate epithelial-mesenchymal transition. Ex vivo treatment of the GBM spheres with TMZ generated numerous variants in cancer driver genes, including TP53 and CDH1, which were mutated in the post-treatment tumor. Conclusions TMZ-induced TP53 gain-of-function mutations can have a driving role in secondary gliosarcoma pathogenesis. Analysis of variants identified in ex vivo TMZ-treated gliomaspheres may have utility in predicting GBM evolutionary trajectories in vivo during standard chemoradiation.
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Affiliation(s)
- Margaret Pain
- Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Huaien Wang
- Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eunjee Lee
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maya Strahl
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Wissam Hamou
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Robert Sebra
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jun Zhu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raymund L Yong
- Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Yao S, Fan LYN, Lam EWF. The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance. Semin Cancer Biol 2017; 50:77-89. [PMID: 29180117 PMCID: PMC6565931 DOI: 10.1016/j.semcancer.2017.11.018] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/30/2017] [Accepted: 11/23/2017] [Indexed: 12/11/2022]
Abstract
The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to ‘classical’ cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors. This is owing to the involvement of FOXO3 and FOXM1 in the regulation of genes linked to crucial drug action-related cellular processes, including stem cell renewal, DNA repair, cell survival, drug efflux, and deregulated mitosis. A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as well as crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.
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Affiliation(s)
- Shang Yao
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Lavender Yuen-Nam Fan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Eric Wing-Fai Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
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Yan H, Wu A. FOXO1 is crucial in glioblastoma cell tumorigenesis and regulates the expression of SIRT1 to suppress senescence in the brain. Mol Med Rep 2017; 17:2535-2542. [PMID: 29207098 DOI: 10.3892/mmr.2017.8146] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/14/2017] [Indexed: 11/06/2022] Open
Abstract
In the present study, the role of Forkhead Box O1 (FOXO1) in glioblastoma (GBM) cell tumorigenesis was examined and the underlying mechanisms were investigated. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were used to analyze the expression of FOXO1 in GBM cell lines (LN18 and T98G) and tissues. Compared with the control groups, FOXO1 was significantly downregulated in the GBM tissues and GBM cell lines (P<0.05). The effects of the expression of FOXO1 on GBM cell proliferation and cell cycle were examined using flow cytometry. The overexpression of FOXO1 markedly inhibited LN18 and T98G cell proliferation and arrested cell cycle at the G0/G1 phase. In addition, FOXO1 facilitated cell senescence through regulation of the expression of sirtuin 1. Epithelial‑mesenchymal transition (EMT) is a complex process, which affects cell growth, invasion and metastasis. The results of the present study revealed that FOXO1 inhibited EMT and metastasis in GBM. These finding revealed a novel mechanism of FOXO1 in the suppression of tumorigenesis and metastasis of GBM cells and suggested that FOXO1 may be a potential therapeutic target for treating GBM.
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Affiliation(s)
- Han Yan
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Anhua Wu
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Hou T, Li Z, Zhao Y, Zhu WG. Mechanisms controlling the anti-neoplastic functions of FoxO proteins. Semin Cancer Biol 2017; 50:101-114. [PMID: 29155239 DOI: 10.1016/j.semcancer.2017.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 10/18/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023]
Abstract
The Forkhead box O (FoxO) proteins comprise a family of evolutionarily conserved transcription factors that predominantly function as tumor suppressors. These proteins assume diverse roles in the cellular anti-neoplastic response, including regulation of apoptosis and autophagy, cancer metabolism, cell-cycle arrest, oxidative stress and the DNA damage response. More recently, FoxO proteins have been implicated in cancer immunity and cancer stem-cell (CSC) homeostasis. Interestingly, in some sporadic sub-populations, FoxO protein function may also be manipulated by factors such as β-catenin whereby they instead can facilitate cancer progression via maintenance of CSC properties or promoting drug resistance or metastasis and invasion. This review highlights the essential biological functions of FoxOs and explores the areas that may be exploited in FoxO protein signaling pathways in the development of novel cancer therapeutic agents.
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Affiliation(s)
- Tianyun Hou
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Zhiming Li
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Ying Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Wei-Guo Zhu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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MiR-629 promotes human pancreatic cancer progression by targeting FOXO3. Cell Death Dis 2017; 8:e3154. [PMID: 29072689 PMCID: PMC5682687 DOI: 10.1038/cddis.2017.525] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 08/21/2017] [Accepted: 09/04/2017] [Indexed: 12/21/2022]
Abstract
The FOXO signaling pathway has been reported to have an important role in human cancer. Expression of miR-629 was markedly upregulated in pancreatic cancer and negatively correlated with FOXO3. Therefore, exploring the regulatory mechanism of miR-629 and FOXO3 signaling may provide valuable clinical targets for pancreatic cancer therapy. In the current study, we found that overexpressing and inhibiting miR-629, respectively, enhanced and reduced the cell proliferation and metastasis of pancreatic cancer cells in vitro and in vivo compared with parental cells or cells transfected with a control vector. Furthermore, we found that miR-629 negatively regulated FOXO3 protein expression and decreased the activity of a luciferase reporter construct containing the FOXO3 3′-untranslated region. These results show that miR-629 regulates FOXO3 at the posttranscriptional level, resulting in enhanced cell proliferation and invasion of pancreatic carcinoma. Furthermore, we found that overexpressing miR-629 enhanced, while inhibiting miR-629 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. A functional polymorphism at miR-629-binding site in the 3′-UTR of FOXO3 gene confers a decreased risk of progression in pancreatic carcinoma. Furthermore, these findings suggest that miR-629 has a vital role in promoting the development of pancreatic cancer and may represent a novel prognostic biomarker and therapeutic target.
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Hannen R, Hauswald M, Bartsch JW. A Rationale for Targeting Extracellular Regulated Kinases ERK1 and ERK2 in Glioblastoma. J Neuropathol Exp Neurol 2017; 76:838-847. [DOI: 10.1093/jnen/nlx076] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Arun RP, Sivanesan D, Vidyasekar P, Verma RS. PTEN/FOXO3/AKT pathway regulates cell death and mediates morphogenetic differentiation of Colorectal Cancer Cells under Simulated Microgravity. Sci Rep 2017; 7:5952. [PMID: 28729699 PMCID: PMC5519599 DOI: 10.1038/s41598-017-06416-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/13/2017] [Indexed: 02/08/2023] Open
Abstract
Gravity is a major physical factor determining the stress and strain around cells. Both in space experiments and ground simulation, change in gravity impacts the viability and function of various types of cells as well as in vivo conditions. Cancer cells have been shown to die under microgravity. This can be exploited for better understanding of the biology and identification of novel avenues for therapeutic intervention. Here, we described the effect of microgravity simulated using Rotational Cell Culture System-High Aspect Ratio Vessel (RCCS-HARV) on the viability and morphological changes of colorectal cancer cells. We observed DLD1, HCT116 and SW620 cells die through apoptosis under simulated microgravity (SM). Gene expression analysis on DLD1 cells showed upregulation of tumor suppressors PTEN and FOXO3; leading to AKT downregulation and further induction of apoptosis, through upregulation of CDK inhibitors CDKN2B, CDKN2D. SM induced cell clumps had elevated hypoxia and mitochondrial membrane potential that led to adaptive responses like morphogenetic changes, migration and deregulated autophagy, when shifted to normal culture conditions. This can be exploited to understand the three-dimensional (3D) biology of cancer in the aspect of stress response. This study highlights the regulation of cell function and viability under microgravity through PTEN/FOXO3/AKT pathway.
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Affiliation(s)
- Raj Pranap Arun
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Divya Sivanesan
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India
| | | | - Rama Shanker Verma
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India.
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Farhan M, Wang H, Gaur U, Little PJ, Xu J, Zheng W. FOXO Signaling Pathways as Therapeutic Targets in Cancer. Int J Biol Sci 2017; 13:815-827. [PMID: 28808415 PMCID: PMC5555100 DOI: 10.7150/ijbs.20052] [Citation(s) in RCA: 339] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/11/2017] [Indexed: 12/11/2022] Open
Abstract
Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl‑XL, bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment.
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Affiliation(s)
- Mohd Farhan
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Haitao Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Uma Gaur
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Peter J Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, 4102 Australia and Xin Hua College, Sun Yat- Sen University, China
| | - Jiangping Xu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Wenhua Zheng
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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Ning Y, Xu M, Cao X, Chen X, Luo X. Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity. Oncol Rep 2017. [DOI: 10.3892/or.2017.5709] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Hay-Koren A, Bialik S, Levin-Salomon V, Kimchi A. Changes in cIAP2, survivin and BimEL expression characterize the switch from autophagy to apoptosis in prolonged starvation. J Intern Med 2017; 281:458-470. [PMID: 28425584 DOI: 10.1111/joim.12616] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Autophagy is a catabolic process involving the engulfment of cytoplasmic content within autophagosomes followed by their delivery to lysosomes. This process is a survival mechanism, enabling cells to cope with nutrient deprivation by degradation and recycling of macromolecules. Yet during continued stress such as prolonged starvation, a switch from autophagy to apoptosis is often detected. OBJECTIVE In this work, we characterized the temporal dynamics of the transition from autophagy towards apoptosis with the aim of elucidating the molecular mechanism regulating the switch from survival autophagy to apoptotic cell death. RESULTS AND CONCLUSIONS We defined an inverse relationship between apoptosis and autophagy spanning a period of 72 h, manifested by the sequential reduction in LC3 lipidation and the activation of caspase-3. The transition to apoptosis correlated with a selective decline in the mRNA and protein levels of two anti-apoptotic IAP family proteins, survivin and cIAP2 and a selective increase in the BH3-only protein, BimEL. This 'molecular signature' was common to several cell lines undergoing the switch from autophagy to apoptosis during prolonged starvation. Mechanistically, the increased BimEL protein levels resulted from its reduced binding to its specific E3 ligase, βTrCP, leading to protein stabilization. Consistent with this, BimEL showed decreased phosphorylation at critical sites previously reported to be essential for binding to the E3 ligase. The decrease in the anti-apoptotic IAPs and the increase in the pro-apoptotic BimEL may thus constitute a molecular switch from autophagy to apoptosis during prolonged starvation.
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Affiliation(s)
- A Hay-Koren
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - S Bialik
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - V Levin-Salomon
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - A Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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FoxR2 promotes glioma proliferation by suppression of the p27 pathway. Oncotarget 2017; 8:56255-56266. [PMID: 28915588 PMCID: PMC5593559 DOI: 10.18632/oncotarget.17447] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 04/14/2017] [Indexed: 02/06/2023] Open
Abstract
FoxR2 plays an important role in the development of many human tumors. However, the effects of FoxR2 on tumorigenicity of human glioma remain unclear. In this study, we investigated the roles of FoxR2 in cell proliferation and invasion of glioma. We found that overexpression of FoxR2 promoted the proliferation, migration and invasion of glioma cells. Knockout of FoxR2 induced G1 arrest by decreasing the expression levels of cyclin D1, cyclin E and p-Rb. Mechanistically, upregulation of FoxR2 increased the level and activity of MMP-2 and decreased the expression of p27. Furthermore, overexpression of FoxR2 decreased the nuclear accumulation of p27. Taken together, these results indicate that upregulation of FoxR2 may confer enhanced tumorigenicity in glioma cells.
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