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Wang H, Tang Z, Xie K, Hao T, Su G. Roquin-1 interaction with Regnase-1 inhibits the progression of rheumatoid arthritis via suppressing FGF2 expression and NF-κB pathway. Inflamm Res 2025; 74:55. [PMID: 40097661 DOI: 10.1007/s00011-025-02012-9] [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: 09/05/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 03/19/2025] Open
Abstract
OBJECTIVE This study aimed to explore the effect of Roquin-1 on rheumatoid arthritis (RA) and its potential mechanisms. METHODS Firstly, we used TNF-α to stimulate fibroblast-like synoviocytes (FLSs) to establish an in vitro model of RA. Moreover, a rat model of RA was established with bovine type II collagen and complete Freund's adjuvant. EdU and transwell assays were applied for evaluating the proliferation and migration of FLSs. The multiple mRNA and proteins expressions in FLSs and rats synovial tissues were measured using qRT-PCR, ELISA, western blot, immunohistochemistry staining and immunofluorescence staining. Double immunofluorescence staining and co-IP assay were used to validate the protein interaction between Roquin-1 and Regnase-1. Additionally, cycloheximide (CHX) chase assay was applied for assessing the degradation of fibroblast growth factor 2 (FGF2). Besides, the state of synovial hyperplasia and articular cartilage were also evaluated using HE and Safranin O/Fast Green staining. RESULTS The mRNA and protein expressions of Roquin-1 were significantly reduced in TNF-α-stimulated FLSs and the synovial tissues of RA rats. Roquin-1 interacted with Regnase-1 to promote FGF2 degradation and further inhibit the proliferation, migration and inflammation response in TNF-α-stimulated FLSs. Moreover, we also demonstrated that Roquin-1 interacted with Regnase-1 to inhibit NF-κB pathway via suppressing FGF2 expression in TNF-α-stimulated FLSs. In addition, Roquin-1 suppressed inflammatory response in RA rats. CONCLUSION Our findings demonstrated that Roquin-1 could interact with Regnase-1 to inhibit the progression of RA via suppressing FGF2 expression and NF-κB pathway.
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Affiliation(s)
- Hui Wang
- Department of Rheumatology, The Fourth Hospital of Jinan, Jinan, 250031, Shandong, People's Republic of China
| | - Zizheng Tang
- Department of Rheumatology, The Fourth Hospital of Jinan, Jinan, 250031, Shandong, People's Republic of China
| | - Kangqi Xie
- Department of Rheumatology, The Fourth Hospital of Jinan, Jinan, 250031, Shandong, People's Republic of China
| | - Tiantian Hao
- Department of Rheumatology, The Fourth Hospital of Jinan, Jinan, 250031, Shandong, People's Republic of China
| | - Gang Su
- Department of Science and Education and Foreign Affairs, The Fourth Hospital of Jinan, No. 50 Shifan Road, Jinan, 250031, Shandong, People's Republic of China.
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Yang Z, Man J, Liu Y, Zhang H, Wu D, Shao D, Hao B, Wang S. Study on the Alleviating Effect and Potential Mechanism of Ethanolic Extract of Limonium aureum (L.) Hill. on Lipopolysaccharide-Induced Inflammatory Responses in Macrophages. Int J Mol Sci 2023; 24:16272. [PMID: 38003461 PMCID: PMC10671607 DOI: 10.3390/ijms242216272] [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: 10/23/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Inflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.
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Affiliation(s)
- Zhen Yang
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Jingyuan Man
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China;
| | - Yu Liu
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Hongjuan Zhang
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Di Wu
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Dan Shao
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Baocheng Hao
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
| | - Shengyi Wang
- Key Laboratory of New Animal Drug Project, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Z.Y.); (Y.L.); (H.Z.); (D.W.); (D.S.)
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3
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Juengpanich S, Li S, Yang T, Xie T, Chen J, Shan Y, Lee J, Lu Z, Chen T, Zhang B, Cao J, Hu J, Yu J, Wang Y, Topatana W, Gu Z, Cai X, Chen M. Pre-activated nanoparticles with persistent luminescence for deep tumor photodynamic therapy in gallbladder cancer. Nat Commun 2023; 14:5699. [PMID: 37709778 PMCID: PMC10502062 DOI: 10.1038/s41467-023-41389-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 09/01/2023] [Indexed: 09/16/2023] Open
Abstract
Phototherapy of deep tumors still suffers from many obstacles, such as limited near-infrared (NIR) tissue penetration depth and low accumulation efficiency within the target sites. Herein, stimuli-sensitive tumor-targeted photodynamic nanoparticles (STPNs) with persistent luminescence for the treatment of deep tumors are reported. Purpurin 18 (Pu18), a porphyrin derivative, is utilized as a photosensitizer to produce persistent luminescence in STPNs, while lanthanide-doped upconversion nanoparticles (UCNPs) exhibit bioimaging properties and possess high photostability that can enhance photosensitizer efficacy. STPNs are initially stimulated by NIR irradiation before intravenous administration and accumulate at the tumor site to enter the cells through the HER2 receptor. Due to Pu18 afterglow luminescence properties, STPNs can continuously generate ROS to inhibit NFκB nuclear translocation, leading to tumor cell apoptosis. Moreover, STPNs can be used for diagnostic purposes through MRI and intraoperative NIR navigation. STPNs exceptional antitumor properties combined the advantages of UCNPs and persistent luminescence, representing a promising phototherapeutic strategy for deep tumors.
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Affiliation(s)
- Sarun Juengpanich
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
- School of Medicine, Zhejiang University, 310058, Hangzhou, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Shijie Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
- School of Medicine, Zhejiang University, 310058, Hangzhou, China
| | - Taorui Yang
- Department of Chemistry, Zhejiang Sci-Tech University, 310018, Hangzhou, China
| | - Tianao Xie
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
- School of Medicine, Zhejiang University, 310058, Hangzhou, China
| | - Jiadong Chen
- Department of Chemistry, Zhejiang University, 310016, Hangzhou, China
| | - Yukai Shan
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Jiyoung Lee
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Ziyi Lu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Tianen Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Bin Zhang
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Jiahao Hu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
| | - Jicheng Yu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, 310058, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, China
- Jinhua Institute of Zhejiang University, 321299, Jinhua, China
| | - Yanfang Wang
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China
| | - Win Topatana
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
- School of Medicine, Zhejiang University, 310058, Hangzhou, China.
| | - Zhen Gu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
- Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, 310058, Hangzhou, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, China.
- Jinhua Institute of Zhejiang University, 321299, Jinhua, China.
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, Hangzhou, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
- School of Medicine, Zhejiang University, 310058, Hangzhou, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
- School of Medicine, Zhejiang University, 310058, Hangzhou, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run-Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, China.
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Wang R, Yang JF, Senay TE, Liu W, You J. Characterization of the Impact of Merkel Cell Polyomavirus-Induced Interferon Signaling on Viral Infection. J Virol 2023; 97:e0190722. [PMID: 36946735 PMCID: PMC10134799 DOI: 10.1128/jvi.01907-22] [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: 12/09/2022] [Accepted: 03/05/2023] [Indexed: 03/23/2023] Open
Abstract
Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.
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Affiliation(s)
- Ranran Wang
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - June F. Yang
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Taylor E. Senay
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Wei Liu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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5
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Ni Y, He J, Chalise P. Integration of differential expression and network structure for 'omics data analysis. Comput Biol Med 2022; 150:106133. [PMID: 36179515 DOI: 10.1016/j.compbiomed.2022.106133] [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: 04/08/2022] [Revised: 08/23/2022] [Accepted: 09/18/2022] [Indexed: 11/25/2022]
Abstract
Differential expression (DE) analysis has been routinely used to identify molecular features that are statistically significantly different between distinct biological groups. In recent years, differential network (DN) analysis has emerged as a powerful approach to uncover molecular network structure changes from one biological condition to the other where the molecular features with larger topological changes are selected as biomarkers. Although a large number of DE and a few DN-based methods are available, they have been usually implemented independently. DE analysis ignores the relationship among molecular features while DN analysis does not account for the expression changes at individual level. Therefore, an integrative analysis approach that accounts for both DE and DN is required to identify disease associated key features. Although, a handful of methods have been proposed, there is no method that optimizes the combination of DE and DN. We propose a novel integrative analysis method, DNrank, to identify disease-associated molecular features that leverages the strengths of both DE and DN by calculating a weight using resampling based cross validation scheme within the algorithm. First, differential expression analysis of individual molecular features is carried out. Second, a differential network structure is constructed using the differential partial correlation analysis. Third, the molecular features are ranked in the order of their significances by integrating their DE measures and DN structure using the modified Google's PageRank algorithm. In the algorithm, the optimum combination of DE and DN analyses is achieved by evaluating the prediction performance of top-ranked features utilizing support vector machine classifier with Monte Carlo cross validation. The proposed method is illustrated using both simulated data and three real data sets. The results show that the proposed method has a better performance in identifying important molecular features with respect to predictive discrimination. Also, as compared to existing feature selection methods, the top-ranked features selected by our method had a higher stability in selection. DNrank allows the researchers to identify the disease-associated features by utilizing both expression and network topology changes between two groups.
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Affiliation(s)
- Yonghui Ni
- Department of Biostatistics and Data Science, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA
| | - Jianghua He
- Department of Biostatistics and Data Science, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA
| | - Prabhakar Chalise
- Department of Biostatistics and Data Science, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA.
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Pérez Piñero C, Giulianelli S, Lamb CA, Lanari C. New Insights in the Interaction of FGF/FGFR and Steroid Receptor Signaling in Breast Cancer. Endocrinology 2022; 163:6491899. [PMID: 34977930 DOI: 10.1210/endocr/bqab265] [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: 11/04/2021] [Indexed: 11/19/2022]
Abstract
Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.
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Affiliation(s)
- Cecilia Pérez Piñero
- Instituto de Biología y Medicina Experimental, IBYME CONICET, C1428ADN Ciudad de Buenos Aires, Argentina
| | - Sebastián Giulianelli
- Instituto de Biología y Medicina Experimental, IBYME CONICET, C1428ADN Ciudad de Buenos Aires, Argentina
- Instituto de Biología de Organismos Marinos, IBIOMAR-CCT CENPAT-CONICET, U9120ACD Puerto Madryn, Argentina
| | - Caroline A Lamb
- Instituto de Biología y Medicina Experimental, IBYME CONICET, C1428ADN Ciudad de Buenos Aires, Argentina
| | - Claudia Lanari
- Instituto de Biología y Medicina Experimental, IBYME CONICET, C1428ADN Ciudad de Buenos Aires, Argentina
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FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance. Cancers (Basel) 2021; 13:cancers13225796. [PMID: 34830951 PMCID: PMC8616288 DOI: 10.3390/cancers13225796] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/13/2021] [Accepted: 11/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Deregulation of the FGF/FGFR axis is associated with many types of cancer and contributes to the development of chemoresistance, limiting the effectiveness of current treatment strategies. There are several mechanisms involved in this phenomenon, including cross-talks with other signaling pathways, avoidance of apoptosis, stimulation of angiogenesis, and initiation of EMT. Here, we provide an overview of current research and approaches focusing on targeting components of the FGFR/FGF signaling module to overcome drug resistance during anti-cancer therapy. Abstract Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.
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Tsuji Y, Nonoguchi N, Okuzaki D, Wada Y, Motooka D, Hirota Y, Toho T, Yoshikawa N, Furuse M, Kawabata S, Miyatake SI, Nakamura H, Yamamoto R, Nakamura S, Kuroiwa T, Wanibuchi M. Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression. Sci Rep 2021; 11:22110. [PMID: 34764346 PMCID: PMC8585920 DOI: 10.1038/s41598-021-01475-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022] Open
Abstract
Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.
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Affiliation(s)
- Yuichiro Tsuji
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
| | - Naosuke Nonoguchi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
| | - Daisuke Okuzaki
- grid.136593.b0000 0004 0373 3971Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Yusuke Wada
- grid.261455.10000 0001 0676 0594Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku Ourai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Daisuke Motooka
- grid.136593.b0000 0004 0373 3971Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Yuki Hirota
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Taichiro Toho
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Nobuhiko Yoshikawa
- Department of Radiology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Motomasa Furuse
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Shinji Kawabata
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Shin-Ichi Miyatake
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan ,Division for Advanced Medical Development, Cancer Center, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Hiroyuki Nakamura
- grid.32197.3e0000 0001 2179 2105Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503 Japan
| | - Ryohei Yamamoto
- grid.261455.10000 0001 0676 0594Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku Ourai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Shota Nakamura
- grid.136593.b0000 0004 0373 3971Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Toshihiko Kuroiwa
- Department of Neurosurgery, Tesseikai Neurosurgical Hospital, 28-1, Nakanohommachi, Shijyonawate, Osaka 575-8511 Japan
| | - Masahiko Wanibuchi
- Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
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Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88. Blood 2021; 137:2495-2508. [PMID: 33197938 DOI: 10.1182/blood.2020008414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/30/2020] [Indexed: 01/12/2023] Open
Abstract
The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
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10
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Santolla MF, Talia M, Maggiolini M. S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells. Int J Mol Sci 2021; 22:ijms22094720. [PMID: 33946884 PMCID: PMC8124532 DOI: 10.3390/ijms22094720] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype characterized by poor clinical outcome. In recent years, numerous advancements have been made to better understand the biological landscape of TNBC, though appropriate targets still remain to be determined. In the present study, we have determined that the expression levels of FGF2 and S100A4 are higher in TNBC with respect to non-TNBC patients when analyzing “The Invasive Breast Cancer Cohort of The Cancer Genome Atlas” (TCGA) dataset. In addition, we have found that the gene expression of FGF2 is positively correlated with S100A4 in TNBC samples. Performing quantitative PCR, Western blot, CRISPR/Cas9 genome editing, promoter studies, immunofluorescence analysis, subcellular fractionation studies, and ChIP assays, we have also demonstrated that FGF2 induces in TNBC cells the upregulation and secretion of S100A4 via FGFR1, along with the ERK1/2–AKT–c-Rel transduction signaling. Using conditioned medium from TNBC cells stimulated with FGF2, we have also ascertained that the paracrine activation of the S100A4/RAGE pathway triggers angiogenic effects in vascular endothelial cells (HUVECs) and promotes the migration of cancer-associated fibroblasts (CAFs). Collectively, our data provide novel insights into the action of the FGF2/FGFR1 axis through S100A4 toward stimulatory effects elicited in TNBC cells.
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MESH Headings
- Antigens, Neoplasm/physiology
- Cell Movement/drug effects
- Culture Media, Conditioned/pharmacology
- Female
- Fibroblast Growth Factor 2/pharmacology
- Fibroblast Growth Factor 2/physiology
- Fibroblasts/pathology
- Gene Expression Regulation, Neoplastic/physiology
- Human Umbilical Vein Endothelial Cells
- Humans
- Mitogen-Activated Protein Kinases/physiology
- Neoplasm Proteins/physiology
- Neovascularization, Pathologic/physiopathology
- Paracrine Communication
- Protein Kinase Inhibitors/pharmacology
- Proto-Oncogene Proteins c-rel/physiology
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/physiology
- S100 Calcium-Binding Protein A4/physiology
- Signal Transduction/drug effects
- Signal Transduction/physiology
- Triple Negative Breast Neoplasms/blood supply
- Triple Negative Breast Neoplasms/physiopathology
- Tumor Cells, Cultured
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11
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Lin K, Rong Y, Chen D, Zhao Z, Bo H, Qiao A, Hao X, Wang J. Combination of Ruthenium Complex and Doxorubicin Synergistically Inhibits Cancer Cell Growth by Down-Regulating PI3K/AKT Signaling Pathway. Front Oncol 2020; 10:141. [PMID: 32133289 PMCID: PMC7041628 DOI: 10.3389/fonc.2020.00141] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 01/27/2020] [Indexed: 01/21/2023] Open
Abstract
Combinational use of drugs has been a common strategy in cancer treatment because of synergistic advantages in reducing dose and toxicity, minimizing or delaying drug resistance. To improve the efficacy of chemotherapy, various potential combinations have been investigated. Ruthenium complex is considered a potential alternative of the platinum-based drugs due to its significant efficacy and safety. Previously, we reported that ruthenium(II) complex (Δ-Ru1) has great anticancer potential and minor toxicity toward normal tissues. However, the therapeutic efficacy and mechanism of action of ruthenium(II) complex combined with other anticancer drugs is still unknown. Here, we investigated the combinational effect of Δ-Ru1 and doxorubicin in different cancer cells. The data assessed by Chou-Talalay method showed significant synergism in MCF-7 cells. Furthermore, the results in antiproliferation efficacy indicated that the combination showed strong cytotoxicity and increasing apoptosis of MCF-7 cells in 2D and 3D multicellular tumor spheroids (MCTSs). Significant inhibition of MCF-7 cells accompanied with increased ROS generation was observed. Furthermore, the expression of PI3K/AKT was significantly down-regulated, while the expression of PTEN was strongly up-regulated in cells treated with combination of Δ-Ru1 and doxorubicin. The expression of NF-κB and XIAP decreased while the expression of P53 increased and associated with apoptosis. These findings suggest that the combination of ruthenium complex and doxorubicin has a significant synergistic effect by down-regulating the PI3K/AKT signaling pathway in MCF-7 cells. This study may trigger more research in ruthenium complex and combination therapy that will be able to provide opportunities for developing better therapeutics for cancer treatment.
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Affiliation(s)
- Ke Lin
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Rong
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dan Chen
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zizhuo Zhao
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huaben Bo
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Aimin Qiao
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaojuan Hao
- Manufacturing, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC, Australia
| | - Jinquan Wang
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
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12
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Yamawaki Y, Shirawachi S, Mizokami A, Nozaki K, Ito H, Asano S, Oue K, Aizawa H, Yamawaki S, Hirata M, Kanematsu T. Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice. Neurochem Int 2019; 131:104563. [PMID: 31589911 DOI: 10.1016/j.neuint.2019.104563] [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] [Received: 03/03/2019] [Revised: 09/09/2019] [Accepted: 10/02/2019] [Indexed: 11/29/2022]
Abstract
Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions.
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Affiliation(s)
- Yosuke Yamawaki
- Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan; Laboratory of Advanced Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan
| | - Satomi Shirawachi
- Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Akiko Mizokami
- OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan
| | - Kanako Nozaki
- Department of Neurobiology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hikaru Ito
- Department of Neurobiology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan; Center for Experimental Animals, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Satoshi Asano
- Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Kana Oue
- Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan; Department of Dental Anesthesiology, Division of Applied Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Hidenori Aizawa
- Department of Neurobiology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shigeto Yamawaki
- Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masato Hirata
- Oral Medicine Research Center, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan
| | - Takashi Kanematsu
- Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan; Department of Cell Biology and Pharmacology, Faculty of Dental Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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13
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Li X, Guo S, Xiong XK, Peng BY, Huang JM, Chen MF, Wang FY, Wang JN. Combination of quercetin and cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway. J Cancer 2019; 10:4509-4521. [PMID: 31528215 PMCID: PMC6746132 DOI: 10.7150/jca.31045] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 04/24/2019] [Indexed: 12/28/2022] Open
Abstract
While cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with oral squamous cell carcinoma (OSCC), the cisplatin-resistance poses a major challenge for its clinical application. Recent studies have shown that quercetin, a natural flavonoid found in various plants and foods possesses an anti-cancer effect. The following study examined the combined effect of quercetin and cisplatin on OSCC apoptosis in vitro and in vivo (using a mice tumor model). We found that quercetin promotes cisplatin-induced apoptosis in human OSCC (cell lines Tca-8113 and SCC-15) by down-regulating NF-κB. Pretreatment of cancer cells with quercetin inhibited the phosphorylation Akt and IKKβ, and led to the suppression of NF-κB and anti-apoptotic protein xIAP. In addition, we observed that the pretreatment of cancer cells with quercetin improves extrinsic and intrinsic apoptosis by activating caspase-8 and caspase-9, respectively. Our in vivo data also indicated that the combination of quercetin and cisplatin may inhibit the xenograft growth in mice. To sum up, our results provide a new evidence for the application of quercetin and cisplatin in OSCC therapy.
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Affiliation(s)
- Xin Li
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Shu Guo
- State Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, South China Institute of Environmental Sciences, Ministry of Environmental Protection, Guangzhou, Guangdong Province, P.R. China, 510655
| | - Xi-Kun Xiong
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Bao-Ying Peng
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Jun-Ming Huang
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Mei-Fen Chen
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Feng-Yan Wang
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Jian-Ning Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, 56, Ling Yuan Xi Road, Guangzhou, Guangdong Province, P.R. China, 510055
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14
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Ahmed M, Legrand C, Yagüe Relimpio A, Beretta CA, Muschko A, Wegehingel S, Müller HM, Sehr P, Will DW, Lewis JD, Nickel W. A time-resolved live cell imaging assay to identify small molecule inhibitors of FGF2 signaling. FEBS Lett 2019; 593:2162-2176. [PMID: 31135968 DOI: 10.1002/1873-3468.13462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/18/2019] [Accepted: 05/24/2019] [Indexed: 11/10/2022]
Abstract
Fibroblast growth factor 2 (FGF2) is a cell survival factor with crucial functions in tumor-induced angiogenesis. Here, we describe a novel time-resolved FGF2 signaling assay based upon live cell imaging of neuroblastoma cells. To validate this system, we tested 8960 small molecules for inhibition of FGF2 signaling with kinetic resolution. Hit compounds were validated in dose-response experiments for FGF2 signaling, FGF receptor antagonism, downstream ERK phosphorylation and FGF2-dependent chemoresistance in a cellular leukemia model system. The new screening system for FGF2 signaling inhibitors has unique features, deselecting compounds with pleiotropic effects on cell proliferation and, along with the experimental pipeline reported, great potential for the discovery of new classes of FGF2 signaling inhibitors that block FGF2 dependent tumor cell survival.
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Affiliation(s)
| | | | | | - Carlo A Beretta
- CellNetworks Math-Clinic Core Facility, BioQuant, Heidelberg University, Germany
| | | | | | | | - Peter Sehr
- European Molecular Biology Laboratory, Heidelberg, Germany
| | - David W Will
- European Molecular Biology Laboratory, Heidelberg, Germany
| | - Joe D Lewis
- European Molecular Biology Laboratory, Heidelberg, Germany
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15
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Dysregulation of Krüppel-like factor 12 in the development of endometrial cancer. Gynecol Oncol 2018; 152:177-184. [PMID: 30482501 DOI: 10.1016/j.ygyno.2018.10.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/15/2018] [Accepted: 10/22/2018] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Endometrial cancer (EC) remains a malignancy with poor survival outcome. To investigate the role of Krüppel-like factor 12 (KLF12), a transcription factor, in the progression of human EC. METHODS Immunohistochemistry, real time-PCR and western blot analysis of KLF12 expression in EC patients' tissues. Bioinformatics analysis revealed the clinical importance of KLF12 expression and survival ratio. Overexpression of KLF12 was generated using the ViraPower Adenoviral Expression System in EC cell lines. Cell viability assay, cell apoptosis assay and cell migration assay were used to determine cell proliferation, cell apoptosis and cell migration, respectively. Western blot analysis was carried out to determine the protein levels in cell lines and animal tissues. RESULTS The expression of KLF12 was observed to be much higher in human EC tissues compared with normal endometrium. Moreover, KLF12 expression was correlated positively with disease recurrence and was also associated with decreased survival probability. The overexpression of KLF12 in EC cell lines resulted in increased cell proliferation, decreased cell apoptosis and enhanced cell migration. Furthermore, overexpression of KLF12 also increased tumor size in vivo. Moreover, up-regulation of KLF12 dramatically increased the expression levels of MMP2, MMP9, pAKT S473 and CCND1. Our research reveals that overexpressed KLF12 contributes the growth of EC tumor by activating AKT signaling and increasing CCND1expression level. CONCLUSIONS To our knowledge, this is the first study to explore the significance of KLF12 in the development of EC, and KLF12 is expected to provide a novel potential therapeutic target for EC treatment.
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16
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Feng Z, Xia Y, Gao T, Xu F, Lei Q, Peng C, Yang Y, Xue Q, Hu X, Wang Q, Wang R, Ran Z, Zeng Z, Yang N, Xie Z, Yu L. The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis. Cell Death Dis 2018; 9:1006. [PMID: 30258182 PMCID: PMC6158270 DOI: 10.1038/s41419-018-1046-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 02/08/2023]
Abstract
Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood-brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.
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Affiliation(s)
- Zhanzhan Feng
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Yong Xia
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Tiantao Gao
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Fuyan Xu
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Qian Lei
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Cuiting Peng
- School of Chemical Engineering, Sichuan University, 610041, Chengdu, China
| | - Yufei Yang
- Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd., 610041, Chengdu, China
| | - Qiang Xue
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Xi Hu
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Qianqian Wang
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Ranran Wang
- West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Zhiqiang Ran
- West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Zhilin Zeng
- West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Nan Yang
- West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Zixin Xie
- West China School of Pharmacy, Sichuan University, 610041, Chengdu, China
| | - Luoting Yu
- Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China.
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17
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Wang C, Ke Y, Liu S, Pan S, Liu Z, Zhang H, Fan Z, Zhou C, Liu J, Wang F. Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling in prostate cancer cells. J Biol Chem 2018; 293:14839-14849. [PMID: 30093411 DOI: 10.1074/jbc.ra118.002907] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 07/25/2018] [Indexed: 01/30/2023] Open
Abstract
Initiation of expression of fibroblast growth factor receptor 1 (FGFR1) concurrent with loss of FGFR2 expression is a well-documented event in the progression of prostate cancer (PCa). Although it is known that some FGFR isoforms confer advantages in cell proliferation and survival, the mechanism by which the subversion of different FGFR isoforms contributes to PCa progression is incompletely understood. Here, we report that fibroblast growth factor (FGF) promotes NF-κB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-κB signaling in PCa cells. Of note, the three common signaling pathways downstream of FGFR1 kinase, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K/AKT), and phosphoinositide phospholipase Cγ (PLCγ), were not required for FGF-mediated NF-κB signaling. Instead, transforming growth factor β-activating kinase 1 (TAK1), a central regulator of the NF-κB pathway, was required for FGFR1 to stimulate NF-κB signaling. Moreover, we found that FGFR1 promotes NF-κB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-κB activation. Consistently, Fgfr1 ablation in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model reduced inflammation in the tumor microenvironment. In contrast, activation of the FGFR1 kinase in the juxtaposition of chemical-induced dimerization (CID) and kinase 1 (JOCK1) mouse model increased inflammation. As inflammation plays an important role in PCa initiation and progression, these findings suggest that ectopically expressed FGFR1 promotes PCa progression, at least in part, by increasing inflammation in the tumor microenvironment.
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Affiliation(s)
- Cong Wang
- From School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China, .,the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843
| | - Yuepeng Ke
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843
| | - Shaoyou Liu
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843.,the Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510000, China
| | - Sharon Pan
- the Gastroenterology and Hepatology Division, Seattle Children's Hospital, Seattle, Washington 98105
| | - Ziying Liu
- From School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.,the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843
| | - Hui Zhang
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843.,the Second Affiliated Hospital of South China University of Technology, Guangzhou 510641, China, and
| | - Zhichao Fan
- From School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Changyi Zhou
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843.,College of Food and Bioengineering, Jimei University, Xiamen 361021, China
| | - Junchen Liu
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843
| | - Fen Wang
- the Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas 77843,
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18
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Benham V, Chakraborty D, Bullard B, Bernard JJ. A role for FGF2 in visceral adiposity-associated mammary epithelial transformation. Adipocyte 2018; 7:113-120. [PMID: 29561195 DOI: 10.1080/21623945.2018.1445889] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Obesity is a leading risk factor for post-menopausal breast cancer, and this is concerning as 40% of cancer diagnoses in 2014 were associated with overweight/obesity. Despite this epidemiological link, the underlying mechanism responsible is unknown. We recently published that visceral adipose tissue (VAT) releases FGF2 and stimulates the transformation of skin epithelial cells. Furthermore, obesity is differentially associated with many epithelial cancers, and this mechanistic link could be translational. As FGF2 and FGFR1 are implicated in breast cancer progression, we hypothesize that VAT-derived FGF2 plays a translational role in promoting adiposity-associated mammary epithelial cell transformation. In this brief report, data suggest that FGF2/FGFR1 signaling is a potential mechanistic link in VAT-stimulated transformation of breast epithelial cells.
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Affiliation(s)
- Vanessa Benham
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Debrup Chakraborty
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Blair Bullard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Jamie J. Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
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Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production. Oncotarget 2018; 7:80275-80287. [PMID: 27852059 PMCID: PMC5348319 DOI: 10.18632/oncotarget.13282] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 11/07/2016] [Indexed: 02/07/2023] Open
Abstract
Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-κB-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.
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Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/06/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
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21
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Jing Q, Wang Y, Liu H, Deng X, Jiang L, Liu R, Song H, Li J. FGFs: crucial factors that regulate tumour initiation and progression. Cell Prolif 2016; 49:438-47. [PMID: 27383016 DOI: 10.1111/cpr.12275] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 06/13/2016] [Indexed: 02/05/2023] Open
Abstract
Fibroblast growth factors (FGFs) are crucial signalling molecules involved in normal cell growth, differentiation and proliferation. Over the past few decades, a large body of research has illustrated effects of individual FGFs on tumour initiation and progression. Tumour development is commonly accompanied with generation of new blood and lymph vessels, which support enhanced cell proliferation. Moreover, acquisition of tumour cells of the epithelial-mesenchymal transition (EMT) phenotype, enhances tumour cell migration and invasion potentials, crucial steps in tumour metastasis. This review summarizes recent findings concerning roles of FGFs in angiogenesis, lymphangiogenesis and EMT.
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Affiliation(s)
- Qian Jing
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Yuanyuan Wang
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Hao Liu
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Xiaowei Deng
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Lin Jiang
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Rui Liu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Haixing Song
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Jingyi Li
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
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22
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Regulation of FGF signaling: Recent insights from studying positive and negative modulators. Semin Cell Dev Biol 2016; 53:101-14. [DOI: 10.1016/j.semcdb.2016.01.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 01/19/2016] [Indexed: 11/19/2022]
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23
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Phuong NTT, Kim SK, Im JH, Yang JW, Choi MC, Lim SC, Lee KY, Kim YM, Yoon JH, Kang KW. Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells. Oncotarget 2016. [PMID: 26418898 DOI: 10.18632/oncotarget.5298.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-κB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-κB inhibition but not by c-Jun/AP-1 or Nrf2 knock-down. Interestingly, the expression levels of microRNA (miR)-146a and -146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased NF-κB-mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation in TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to 4-hydroxytamoxifen in TAMR-MCF-7 cells.
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Affiliation(s)
- Nguyen Thi Thuy Phuong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Sang Kyum Kim
- College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea
| | - Ji Hye Im
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Jin Won Yang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Min Chang Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Sung Chul Lim
- Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, South Korea
| | - Kwang Yeol Lee
- College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea
| | - Young-Mi Kim
- College of Pharmacy, Hanyang University, Ansan 426-791, South Korea
| | - Jeong Hoon Yoon
- Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, South Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
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Phuong NTT, Kim SK, Im JH, Yang JW, Choi MC, Lim SC, Lee KY, Kim YM, Yoon JH, Kang KW. Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells. Oncotarget 2016; 7:13902-16. [PMID: 26418898 PMCID: PMC4924687 DOI: 10.18632/oncotarget.5298] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 09/04/2015] [Indexed: 02/07/2023] Open
Abstract
We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-κB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-κB inhibition but not by c-Jun/AP-1 or Nrf2 knock-down. Interestingly, the expression levels of microRNA (miR)-146a and -146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased NF-κB-mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation in TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to 4-hydroxytamoxifen in TAMR-MCF-7 cells.
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Affiliation(s)
- Nguyen Thi Thuy Phuong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Sang Kyum Kim
- College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea
| | - Ji Hye Im
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Jin Won Yang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Min Chang Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
| | - Sung Chul Lim
- Department of Pathology, College of Medicine, Chosun University, Gwangju 501-759, South Korea
| | - Kwang Yeol Lee
- College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea
| | - Young-Mi Kim
- College of Pharmacy, Hanyang University, Ansan 426-791, South Korea
| | - Jeong Hoon Yoon
- Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, South Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
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25
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Sigala F, Savvari P, Liontos M, Sigalas P, Pateras IS, Papalampros A, Basdra EK, Kolettas E, Papavassiliou AG, Gorgoulis VG. Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF-κB pathway. J Cell Mol Med 2016; 14:2273-80. [PMID: 20455997 PMCID: PMC3822568 DOI: 10.1111/j.1582-4934.2010.01082.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and NO-induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analyzed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-kappaB (NF-kappaB) activation. Collectively, our data demonstrate a novel NF-kappaB-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability.
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Affiliation(s)
- Fragiska Sigala
- Molecular Carcinogenesis Group, Laboratory of Histology and Embryology, Medical School, University of Athens, Athens, Greece
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26
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Hong KK, Gwak MJ, Song J, Kim NI. Nuclear factor-κB pathway activation and phosphatase and tensin homolog downregulation in psoriasis. Br J Dermatol 2015; 174:433-5. [PMID: 26302365 DOI: 10.1111/bjd.14106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- K-K Hong
- Department of Dermatology, Kyung Hee University Medical Centre, Hoegi-dong, Dongdaemun-gu, Seoul, Korea
| | - M-J Gwak
- Department of Dermatology, Kyung Hee University Medical Centre, Hoegi-dong, Dongdaemun-gu, Seoul, Korea
| | - J Song
- Department of Dermatology, Kyung Hee University Medical Centre, Hoegi-dong, Dongdaemun-gu, Seoul, Korea
| | - N-I Kim
- Department of Dermatology, Kyung Hee University Medical Centre, Hoegi-dong, Dongdaemun-gu, Seoul, Korea
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27
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Zhang X, Wang Y, Wang J, Sun F. Protein-protein interactions among signaling pathways may become new therapeutic targets in liver cancer (Review). Oncol Rep 2015; 35:625-38. [PMID: 26717966 DOI: 10.3892/or.2015.4464] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 07/06/2015] [Indexed: 11/05/2022] Open
Abstract
Numerous signaling pathways have been shown to be dysregulated in liver cancer. In addition, some protein-protein interactions are prerequisite for the uncontrolled activation or inhibition of these signaling pathways. For instance, in the PI3K/AKT signaling pathway, protein AKT binds with a number of proteins such as mTOR, FOXO1 and MDM2 to play an oncogenic role in liver cancer. The aim of the present review was to focus on a series of important protein-protein interactions that can serve as potential therapeutic targets in liver cancer among certain important pro-carcinogenic signaling pathways. The strategies of how to investigate and analyze the protein-protein interactions are also included in this review. A survey of these protein interactions may provide alternative therapeutic targets in liver cancer.
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Affiliation(s)
- Xiao Zhang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Yulan Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Jiayi Wang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
| | - Fenyong Sun
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
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Park SY, Lee YJ, Cho EJ, Shin CY, Sohn UD. Intrinsic resistance triggered under acid loading within normal esophageal epithelial cells: NHE1- and ROS-mediated survival. J Cell Physiol 2015; 230:1503-14. [DOI: 10.1002/jcp.24896] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 12/12/2014] [Indexed: 01/27/2023]
Affiliation(s)
- Sun Young Park
- Department of Pharmacology; College of Pharmacy; Chung-Ang University; Seoul South Korea
| | - Yeon Joo Lee
- Department of Pharmacology; College of Pharmacy; Chung-Ang University; Seoul South Korea
| | - Eun Jeong Cho
- Department of Pharmacology; College of Pharmacy; Chung-Ang University; Seoul South Korea
| | - Chang Yell Shin
- Dong-A Pharmaceutical; Research Center; Yongin-si Gyeonggi-do South Korea
| | - Uy Dong Sohn
- Department of Pharmacology; College of Pharmacy; Chung-Ang University; Seoul South Korea
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29
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Abstract
In MCF-7 breast cancer cells epidermal growth factor (EGF) induces cell proliferation, whereas heregulin (HRG)/neuregulin (NRG) induces irreversible phenotypic changes accompanied by lipid accumulation. Although these changes in breast cancer cells resemble processes that take place in the tissue, there is no understanding of signalling mechanisms regulating it. To identify molecular mechanisms mediating this cell-fate decision process, we applied different perturbations to pathways activated by these growth factors. The results demonstrate that phosphoinositide 3 (PI3) kinase (PI3K) and mammalian target of rapamycin (mTOR) complex (mTORC)1 activation is necessary for lipid accumulation that can also be induced by insulin, whereas stimulation of the extracellular-signal-regulated kinase (ERK) pathway is surprisingly dispensable. Interestingly, insulin exposure, as short as 4 h, was sufficient for triggering the lipid accumulation, whereas much longer treatment with HRG was required for achieving similar cellular response. Further, activation patterns of ATP citrate lyase (ACLY), an enzyme playing a central role in linking glycolytic and lipogenic pathways, suggest that lipids accumulated within cells are produced de novo rather than absorbed from the environment. In the present study, we demonstrate that PI3K pathway regulates phenotypic changes in breast cancer cells, whereas signal intensity and duration is crucial for cell fate decisions and commitment. Our findings reveal that MCF-7 cell fate decisions are controlled by a network of positive and negative regulators of both signalling and metabolic pathways. Excessive production and accumulation of lipids is often observed in breast cancer tissue. In the current study, we investigate signalling mechanisms regulating this process using a model cell line.
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Bizen N, Inoue T, Shimizu T, Tabu K, Kagawa T, Taga T. A growth-promoting signaling component cyclin D1 in neural stem cells has antiastrogliogenic function to execute self-renewal. Stem Cells 2015; 32:1602-15. [PMID: 24302516 DOI: 10.1002/stem.1613] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 10/11/2013] [Accepted: 10/21/2013] [Indexed: 11/07/2022]
Abstract
Self-renewing proliferation of neural stem cells (NSCs) is intimately linked to the inhibition of neuronal and glial differentiation, however, their molecular linkage has been poorly understood. We have proposed a model previously explaining partly this linkage, in which fibroblast growth factor 2 (FGF2) and Wnt signals cooperate to promote NSC self-renewal via β-catenin accumulation, which leads to the promotion of proliferation by lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated cyclin D1 expression and at the same time to the inhibition of neuronal differentiation by β-catenin-mediated potentiation of Notch signaling. To fully understand the mechanisms underlying NSC self-renewal, it needs to be clarified how these growth factor signals inhibit glial differentiation as well. Here, we demonstrate that cyclin D1, a NSC growth promoting signaling component and also a common component of FGF2 and Wnt signaling pathways, inhibits astroglial differentiation of NSCs. Interestingly, this effect of cyclin D1 is mediated even though its cell cycle progression activity is blocked. Forced downregulation of cyclin D1 enhances astrogliogenesis of NSCs in culture and in vivo. We further demonstrate that cyclin D1 binds to STAT3, a transcription factor downstream of astrogliogenic cytokines, and suppresses its transcriptional activity on the glial fibrillary acidic protein (Gfap) gene. Taken together with our previous finding, we provide a novel molecular mechanism for NSC self-renewal in which growth promoting signaling components activated by FGF2 and Wnts inhibit neuronal and glial differentiation.
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Affiliation(s)
- Norihisa Bizen
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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31
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Smilax china L. rhizome extract inhibits nuclear factor-κB and induces apoptosis in ovarian cancer cells. Chin J Integr Med 2014; 21:907-15. [DOI: 10.1007/s11655-014-1788-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Indexed: 01/08/2023]
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32
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SUN XIAOLI, JIA YU, WEI YUANYU, LIU SHUAI, YUE BAOHONG. Gene expression profiling of HL-60 cells following knockdown of nucleostemin using DNA microarrays. Oncol Rep 2014; 32:739-47. [DOI: 10.3892/or.2014.3240] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 04/29/2014] [Indexed: 11/05/2022] Open
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Wu Y, Kim J, Elshimali Y, Sarkissyan M, Vadgama JV. Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice. BMC Cancer 2014; 14:266. [PMID: 24742286 PMCID: PMC4021211 DOI: 10.1186/1471-2407-14-266] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 03/17/2014] [Indexed: 11/10/2022] Open
Abstract
Background Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Hence, transgenic mice were created to explore the oncogenic role of Akt1 in the development of mammary tumors. Methods The transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of the MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used to induce tumor formation. Results The MMTV driven myr-Akt1 transgene expression was detected primarily in the mammary glands, uterus, and ovaries. The expression level increased significantly in lactating mice, suggesting that the response was hormone dependent. The total Akt expression level in the mammary gland was also higher in the lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in the ovaries of the transgenic mice caused significant increase in circulating estrogen levels, even at the post-lactation stage. Expression of myr-Akt1 in mammary glands alone did not increase the frequency of tumor formation. However, there was an increased susceptibility of forming mammary tumors induced by DMBA in the transgenic mice, especially in mice post-lactation. Within 34 weeks, DMBA induced mammary tumors in 42.9% of transgenic mice post-lactation, but not in wild-type mice post-lactation. The myr-Akt1 mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and epidermal growth factor receptor (EGFR). In addition, Cyclin D1 was more frequently up-regulated in mammary tumors from transgenic mice compared to tumors from wild-type mice. Overexpression of Cyclin D1, however, was not completely dependent on activated Akt1. Interestingly, mammary tumors that had metastasized to secondary sites had increased expression of Twist and Slug, but low expression of Cyclin D1. Conclusions In summary, the MMTVmyr-Akt1 transgenic mouse model could be useful to study mechanisms of ER-positive breast tumor development.
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Affiliation(s)
| | | | | | | | - Jaydutt V Vadgama
- Division of Cancer Research and Training, Charles R, Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, CA 90059, USA.
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Li Y, Man X, You L, Xiang Q, Li H, Xu B, Chen Z, Zhang X, Lian S. Downregulation of PTEN expression in psoriatic lesions. Int J Dermatol 2013; 53:855-60. [PMID: 24168180 DOI: 10.1111/ijd.12061] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Yadi Li
- Department of Dermatology; Xuanwu Hospital; Capital Medical University; Beijing China
- Department of Dermatology; Beijing Tongren Hospital; Capital Medical University; Beijing China
| | - Xiaohong Man
- Department of Dermatology; China-Japan Friendship Hospital; Beijing China
| | - Liping You
- Department of Dermatology; China-Japan Friendship Hospital; Beijing China
| | - Qing Xiang
- IInstitute of Clinical Medicine; China-Japan Friendship Hospital; Beijing China
| | - Hongyan Li
- IInstitute of Clinical Medicine; China-Japan Friendship Hospital; Beijing China
| | - Bo Xu
- IInstitute of Clinical Medicine; China-Japan Friendship Hospital; Beijing China
| | - Zhihua Chen
- IInstitute of Clinical Medicine; China-Japan Friendship Hospital; Beijing China
| | - Xiaoyan Zhang
- Department of Dermatology; China-Japan Friendship Hospital; Beijing China
| | - Shi Lian
- Department of Dermatology; Xuanwu Hospital; Capital Medical University; Beijing China
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Lizano P, Rashed E, Kang H, Dai H, Sui X, Yan L, Qiu H, Depre C. The valosin-containing protein promotes cardiac survival through the inducible isoform of nitric oxide synthase. Cardiovasc Res 2013; 99:685-93. [PMID: 23737493 DOI: 10.1093/cvr/cvt136] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
AIMS Expression of the heat shock protein 22 (Hsp22) in the heart stimulates cardiac cell survival through activation of the Akt pathway and expression of the inducible nitric oxide (NO) synthase (iNOS), the mediator of ischaemic preconditioning and the most powerful prophylaxis against cardiac cell death. The goal of the present study was to elucidate the downstream effector by which Hsp22 and Akt increase iNOS expression. We tested both in vivo and in vitro the hypothesis that such an effector is the valosin-containing protein (VCP), an Akt substrate, which activates the transcription factor NF-κB, using a transgenic mouse with cardiac-specific over-expression of Hsp22, as well as isolated rat cardiac myocytes. METHODS AND RESULTS Using two-dimensional gel electrophoresis and mass spectrometry combined with immunoprecipitation, we found that Hsp22 and Akt co-localize and interact together with VCP. Adeno-mediated over-expression of VCP in isolated cardiac myocytes activated NF-κB and dose-dependently increased the expression of iNOS, which was abolished upon NF-κB inhibition. Over-expression of a dominant-negative (DN) mutant of VCP did not increase iNOS expression. VCP, but not its DN mutant, protected against chelerythrine-induced apoptosis, which was suppressed by inhibition of either NF-κB or iNOS. VCP-mediated activation of the NF-κB/iNOS pathway was also prevented upon inhibition of Akt. CONCLUSION We conclude that the Akt substrate, VCP, mediates the increased expression of iNOS downstream from Hsp22 through an NF-κB-dependent mechanism.
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Affiliation(s)
- Paulo Lizano
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, 07103, USA
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Bolisetty S, Jaimes EA. Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci 2013; 14:6306-44. [PMID: 23528859 PMCID: PMC3634422 DOI: 10.3390/ijms14036306] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 03/08/2013] [Accepted: 03/11/2013] [Indexed: 02/06/2023] Open
Abstract
The air that we breathe contains nearly 21% oxygen, most of which is utilized by mitochondria during respiration. While we cannot live without it, it was perceived as a bane to aerobic organisms due to the generation of reactive oxygen and nitrogen metabolites by mitochondria and other cellular compartments. However, this dogma was challenged when these species were demonstrated to modulate cellular responses through altering signaling pathways. In fact, since this discovery of a dichotomous role of reactive species in immune function and signal transduction, research in this field grew at an exponential pace and the pursuit for mechanisms involved began. Due to a significant number of review articles present on the reactive species mediated cell death, we have focused on emerging novel pathways such as autophagy, signaling and maintenance of the mitochondrial network. Despite its role in several processes, increased reactive species generation has been associated with the origin and pathogenesis of a plethora of diseases. While it is tempting to speculate that anti-oxidant therapy would protect against these disorders, growing evidence suggests that this may not be true. This further supports our belief that these reactive species play a fundamental role in maintenance of cellular and tissue homeostasis.
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Affiliation(s)
- Subhashini Bolisetty
- Nephrology Division, University of Alabama at Birmingham, Birmingham, AL 35294, USA; E-Mail:
| | - Edgar A. Jaimes
- Nephrology Division, University of Alabama at Birmingham, Birmingham, AL 35294, USA; E-Mail:
- Veterans Affairs Medical Center, Birmingham, AL 35233, USA
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Zheng J, Hu JD, Chen YY, Chen BY, Huang Y, Zheng ZH, Liu TB. Baicalin induces apoptosis in leukemia HL-60/ADR cells via possible down-regulation of the PI3K/Akt signaling pathway. Asian Pac J Cancer Prev 2013; 13:1119-24. [PMID: 22799292 DOI: 10.7314/apjcp.2012.13.4.1119] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The effect and possible mechanism of traditional Chinese medicine, baicalin, on the PI3K/ Akt signaling pathway in drug-resistant human myeloid leukemia HL-60/ADR cells have been investigated in this current study. METHODS HL-60/ADR cells were treated by 20, 40, 80 μmol/L baicalin followed by cell cycle analysis at 24h. The mRNA expression level of the apoptosis related gene, Bcl-2 and bad, were measured by RT-PCR on cells treated with 80 μmol/L baicalin at 12, 24 and 48hr. Western blot was performed to detect the changes in the expression of the proteins related to HL-60/ADR cell apoptosis and the signaling pathway before and after baicalin treatment, including Bcl-2, PARP, Bad, Caspase 3, Akt, p-Akt, NF-κB, p-NF-κB, mTOR and p-mTOR. RESULTS Sub-G1 peak of HL-60/ADR cells appeared 24 h after 20 μmol/L baicalin treatment, and the ratio increased as baicalin concentration increased. Cell cycle analysis showed 44.9% G0/G1 phase cells 24 h after baicalin treatment compared to 39.6% in the control group. Cells treated with 80 μmol/L baicalin displayed a trend in decreasing of Bcl-2 mRNA expression over time. Expression level of the Bcl-2 and PARP proteins decreased significantly while that of the PARP, Caspase-3, and Bad proteins gradually increased. No significant difference in Akt expression was observed between treated and the control groups. However, the expression levels of p-Akt, NF-κB, p-NF-κB, mTOR and p-mTOR decreased significantly in a time-dependent manner. CONCLUSIONS We conclude that baicalin may induce HL-60/ADR cell apoptosis through the PI3K/AKT signaling pathway.
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Affiliation(s)
- Jing Zheng
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China
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Fuchs Y, Brunwasser M, Haif S, Haddad J, Shneyer B, Goldshmidt-Tran O, Korsensky L, Abed M, Zisman-Rozen S, Koren L, Carmi Y, Apte R, Yang RB, Orian A, Bejar J, Ron D. Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB. Dev Cell 2013; 23:611-23. [PMID: 22975329 DOI: 10.1016/j.devcel.2012.07.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 06/13/2012] [Accepted: 07/17/2012] [Indexed: 12/11/2022]
Abstract
The NF-κB transcription factor controls diverse biological processes. According to the classical model, NF-κB is retained in the cytoplasm of resting cells via binding to inhibitory, IκB proteins and translocates into the nucleus upon their ligand-induced degradation. Here we reveal that Sef, a known tumor suppressor and inhibitor of growth factor signaling, is a spatial regulator of NF-κB. Sef expression is regulated by the proinflammatory cytokines tumor necrosis factor and interleukin-1, and Sef specifically inhibits "classical" NF-κB (p50:p65) activation by these ligands. Like IκBs, Sef sequesters NF-κB in the cytoplasm of resting cells. However, contrary to IκBs, Sef continues to constrain NF-κB nuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown markedly enhances stimulus-induced NF-κB nuclear translocation and consequent activity. This study establishes Sef as a feedback antagonist of proinflammatory cytokines and highlights its potential to regulate the crosstalk between proinflammatory cytokine receptors and receptor tyrosine kinases.
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Affiliation(s)
- Yaron Fuchs
- Department of Biology, Technion, Israel Institute of Technology, Haifa 32000, Israel
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Todorović-Raković N, Vujasinović T, Abu Rabi Z. Selection of clinically useful angiogenesis-related biomarkers: an update. Int J Biol Markers 2012; 27:e65-e81. [PMID: 22307386 DOI: 10.5301/jbm.2012.8989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2011] [Indexed: 11/20/2022]
Abstract
Angiogenesis is a complex phenomenon that involves interaction between growth factors/cytokines and their receptors, and proteolytic enzymes and their inhibitors, which, in addition to and in accordance with their main roles, act together during this multistep process. Cancer angiogenesis is specific, because the same factors that enable angiogenesis are involved in the process of carcinogenesis. The aim of this review was to analyze the current knowledge regarding the significance of selected biomarkers in cancer angiogenesis, with emphasis on their prognostic value in the circulation.
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Affiliation(s)
- Nataša Todorović-Raković
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade - Serbia.
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Oleksowicz L, Liu Y, Bracken RB, Gaitonde K, Burke B, Succop P, Levin L, Dong Z, Lu S. Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer. Prostate 2012; 72:1140-9. [PMID: 22127954 PMCID: PMC3345320 DOI: 10.1002/pros.22463] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Accepted: 11/01/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker. METHODS Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by Western blot and reporter assay. RESULTS We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A receiver operating characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8-10) relative to intermediate Gleason score (6-7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (area under curve, AUC) was 0.73 and 0.74, respectively. CONCLUSION We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision-making and optimize patient management.
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Affiliation(s)
- Leslie Oleksowicz
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Yin Liu
- Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - R. Bruce Bracken
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Krishnanath Gaitonde
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Barbara Burke
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Paul Succop
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Linda Levin
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Zhongyun Dong
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237
| | - Shan Lu
- Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45237
- To whom correspondence should be addressed. Department of Pathology, University of Cincinnati College of Medicine, Building A, Room 259, 2120 East, Galbraith Road, Cincinnati, OH 45237-0507. Phone: 513-558-5109; Fax: 513-558-1312;
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Park SA, Na HK, Surh YJ. Resveratrol suppresses 4-hydroxyestradiol-induced transformation of human breast epithelial cells by blocking IκB kinaseβ-NF-κB signalling. Free Radic Res 2012; 46:1051-7. [DOI: 10.3109/10715762.2012.671940] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Calbindin-D28K inhibits apoptosis in dopaminergic neurons by activation of the PI3-kinase-Akt signaling pathway. Neuroscience 2011; 199:359-67. [PMID: 22020319 DOI: 10.1016/j.neuroscience.2011.09.054] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Revised: 08/13/2011] [Accepted: 09/26/2011] [Indexed: 11/22/2022]
Abstract
Calbindin-D28k (CaBP) has a neuroprotective effect on dopaminergic (DA) neurons in several models of Parkinson's disease. We used the DA cell line MN9D to explore the mechanisms underlying CaBP-mediated protection against the neurotoxin 6-hydroxydopamine (6-OHDA) of DA neurons. In MN9D cells that were transfected with the expression vector pcDNA3-CB containing CaBP cDNA, the expression level of CaBP was significantly increased. After treating with 6-OHDA, a significant decrease in the apoptosis rate of the transfected MN9D cells was noted, as well as an obvious increase in the expression of phosphorylation of Akt (p-Akt); however, no significant change in the expression of total Akt or phospho-p100 (p-p100) occurred after this treatment. After treatment with wortmannin, an inhibitor of the PI3-kinase-Akt (PI-3K/Akt) signal pathway, an increase in the expression level of CaBP was observed, but there were no other obvious changes of the experimental index mentioned previously in the groups transfected with pcDNA3-CB. These studies suggest that CaBP has a significant role in protecting DA cells against the apoptosis induced by 6-OHDA--through PI-3K/Akt signaling pathway--where the non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway might have no relevance.
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Jiang T, Grabiner B, Zhu Y, Jiang C, Li H, You Y, Lang J, Hung MC, Lin X. CARMA3 is crucial for EGFR-Induced activation of NF-κB and tumor progression. Cancer Res 2011; 71:2183-92. [PMID: 21406399 DOI: 10.1158/0008-5472.can-10-3626] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
EGF activates NF-κB, and constitutively activated NF-κB contributes to EGFR mutation-associated tumorigenesis, but it remains unclear precisely how EGFR signaling leads to NF-κB activation. Here we report that CARMA3, a caspase recruitment domain (CARD)-containing scaffold molecule, is required for EGF-induced NF-κB activation. CARMA3 deficiency impaired the activation of the IKK complex following EGF stimulation, resulting in a defect of EGF-induced IκBα phosphorylation and NF-κB activation. We found that CARMA3 and Bcl10 contributed to several characteristics of EGFR-associated malignancy, including proliferation, survival, migration, and invasion. Most importantly, CARMA3 contributed to tumor growth in vivo. Our findings elucidate a crucial link between EGFR-proximal signaling components and the downstream IKK complex, and they suggest a new therapeutic target for treatment of EGFR-driven cancers.
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Affiliation(s)
- Tang Jiang
- Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
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Ma G, Ren Y, Wang K, He J. SRC-3 has a role in cancer other than as a nuclear receptor coactivator. Int J Biol Sci 2011; 7:664-72. [PMID: 21647249 PMCID: PMC3107475 DOI: 10.7150/ijbs.7.664] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 05/01/2011] [Indexed: 01/01/2023] Open
Abstract
Steroid receptor coactivator-3 (SRC-3), also known as AIB1, is a member of the p160 steroid receptor coactivator family. Since SRC-3 was found to be amplified in breast cancer in 1997, the role of SRC-3 in cancer has been broadly investigated. SRC-3 initially was identified as a transcriptional coactivator for nuclear receptors such as the estrogen receptor (ER), involved in the proliferation of hormone-dependent cancers. However, increasing clinical evidence shows that dysregulation of SRC-3 expression in several human hormone-independent cancers is correlated with pathological factors and clinical prognosis. Recently, both in vivo and in vitro studies demonstrate that SRC-3 may influence a number of cancer cellular processes in several ways independent of nuclear receptor signaling. In addition, an SRC-3 transgenic mice model shows that SRC-3 induces tumors in several mouse tissues. These results indicate that the role of SRC-3 in cancer is not just as a nuclear receptor coactivator. The focus of this review is to examine possible SRC-3 roles in cancer, other than as a nuclear receptor coactivator.
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Affiliation(s)
- Gang Ma
- Department of Surgical Oncology, First Affiliated Hospital, Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P. R. China
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Drafahl KA, McAndrew CW, Meyer AN, Haas M, Donoghue DJ. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling. PLoS One 2010; 5:e14412. [PMID: 21203561 PMCID: PMC3008709 DOI: 10.1371/journal.pone.0014412] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 11/24/2010] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. METHODOLOGY/PRINCIPAL FINDINGS Here, we demonstrate an interaction between FGFR4 and IKKβ (Inhibitor of NFκB Kinase β subunit), an essential component in the NFκB pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKKβ in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNFα (Tumor Necrosis Factor α) to activate NFκB pathways, FGFR4 activation results in significant inhibition of NFκB signaling as measured by decreased nuclear NFκB localization, by reduced NFκB transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKKβ kinase activity towards the substrate GST-IκBα in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling. CONCLUSIONS/SIGNIFICANCE These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone.
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Affiliation(s)
- Kristine A. Drafahl
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America
| | - Christopher W. McAndrew
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America
| | - April N. Meyer
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America
| | - Martin Haas
- Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America
| | - Daniel J. Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America
- Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America
- * E-mail:
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Dong Z, Liu Y, Scott KF, Levin L, Gaitonde K, Bracken RB, Burke B, Zhai QJ, Wang J, Oleksowicz L, Lu S. Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. Carcinogenesis 2010; 31:1948-55. [PMID: 20837598 DOI: 10.1093/carcin/bgq188] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden.
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Affiliation(s)
- Zhongyun Dong
- Department of Medicine, University of Cincinnati College of Medicine, 2120 East Galbraith Road, Cincinnati, OH 45237-0507, USA
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Niederberger E, Geisslinger G. Analysis of NF-kappaB signaling pathways by proteomic approaches. Expert Rev Proteomics 2010; 7:189-203. [PMID: 20377387 DOI: 10.1586/epr.10.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
NF-kappaB is a transcription factor that plays important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. Consequently, dysregulations in the NF-kappaB activation cascade have been associated with the pathogenesis of several diseases such as cancer, atherosclerosis and rheumatoid arthritis. Although NF-kappaB signaling pathways have been extensively investigated in this context, its varying components and targets are far from being completely elucidated. There is still an urgent need for the detection of novel NF-kappaB target proteins, novel interaction partners and novel regulators in the activation cascade, in particular with regard to its role in the aforementioned diseases. Therefore, several groups have performed different proteomic approaches to further investigate NF-kappaB signal transduction pathways. Most of these studies have been carried out in the area of cancer research; however, there are also several analyses in the field of inflammatory or autoimmune diseases. Furthermore, there have been a number of basic investigations that principally examined binding partners or so far unknown target proteins of NF-kappaB-related proteins. With these approaches, a number of novel and interesting proteins have been found that interfere with NF-kappaB signal transduction and might have an impact on NF-kappaB-related diseases. The results of these studies are summarized and discussed in this review.
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Affiliation(s)
- Ellen Niederberger
- Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
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Abstract
Reactive oxygen species (ROS) were seen as destructive molecules, but recently, they have been shown also to act as second messengers in varying intracellular signaling pathways. This review concentrates on hydrogen peroxide (H2O2), as it is a more stable ROS, and delineates its role as a survival molecule. In the first part, the production of H2O2 through the NADPH oxidase (Nox) family is investigated. Through careful examination of Nox proteins and their regulation, it is determined how they respond to stress and how this can be prosurvival rather than prodeath. The pathways on which H2O2 acts to enable its prosurvival function are then examined in greater detail. The main survival pathways are kinase driven, and oxidation of cysteines in the active sites of various phosphatases can thus regulate those survival pathways. Regulation of transcription factors such as p53, NF-kappaB, and AP-1 also are reviewed. Finally, prodeath proteins such as caspases could be directly inhibited through their cysteine residues. A better understanding of the prosurvival role of H2O2 in cells, from the why and how it is generated to the various molecules it can affect, will allow more precise targeting of therapeutics to this pathway.
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Affiliation(s)
- Gillian Groeger
- Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork , Cork, Ireland
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Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFalpha promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-kappaB signaling pathway. Bone 2009; 45:367-76. [PMID: 19414075 DOI: 10.1016/j.bone.2009.04.252] [Citation(s) in RCA: 200] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 04/24/2009] [Accepted: 04/25/2009] [Indexed: 12/29/2022]
Abstract
Mesenchymal stem cells are multipotent cells able to differentiate into different mesenchymal lineages. Studies in the past had suggested that two of these mesenchymal differentiation directions, the chondrogenic and the myogenic differentiation, are negatively regulated by the transcription factor NF-kappaB. Although osteogenic differentiation has been extensively studied, the influence of NF-kappaB on this differentiation lineage was not subject of detailed analyses in the past. We have analyzed the consequences of TNF-alpha treatment and genetic manipulation of the NF-kappaB pathway for osteogenic differentiation of hMSCs. Treatment of hMSCs during differentiation with TNF-alpha activates NF-kappaB and this results in enhanced expression of osteogenetic proteins like bone morphogenetic protein2 (BMP-2) and alkaline phosphatase (ALP). In addition, enhanced matrix mineralization was observed. The direct contribution of the NF-kappaB pathway was confirmed in cells that express a constitutively active version of the NF-kappaB-inducing kinase IKK2 (CA-IKK2). The IKK2/NF-kappaB-induced BMP-2 up-regulation results in the enhancement of RUNX2 and Osterix expression, two critical regulators of the osteogenic differentiation program. Interestingly, a genetic block of the NF-kappaB pathway did not interfere with osteogenic differentiation. We conclude that TNFalpha mediated NF-kappaB activation, although not absolutely required for BMP-2 expression and matrix mineralization nevertheless supports osteogenic differentiation and matrix mineralization by increasing BMP-2 expression. Our results therefore suggest that NF-kappaB activation may function in lineage selection during differentiation of hMSCs by fostering osteogenic differentiation at the expense of other differentiation lineages.
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Affiliation(s)
- Katrin Hess
- Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany
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