|
1
|
Zahedifard Z, Mahmoodi S, Ghasemian A. Genetically Engineered Bacteria as a Promising Therapeutic Strategy Against Cancer: A Comprehensive Review. Biotechnol Appl Biochem 2025. [PMID: 39985148 DOI: 10.1002/bab.2738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025]
Abstract
As a significant cause of global mortality, the cancer has also economic impacts. In the era of cancer therapy, mitigating side effects and costs and overcoming drug resistance is crucial. Microbial species can grow inside the tumor microenvironment and inhibit cancer growth through direct killing of tumor cells and immunoregulatory effects. Although microbiota or their products have demonstrated anticancer effects, the possibility of acting as pathogens and exerting side effects in certain individuals is a risk. Hence, several genetically modified/engineered bacteria (GEB) have been developed to this aim with ability of diagnosing and selective targeting and destruction of cancers. Additionally, GEB are expected to be considerably more efficient, safer, more permeable, less costly, and less invasive theranostic approaches compared to wild types. Potential GEB strains such as Escherichia coli (Nissle 1917, and MG1655), Salmonella typhimurium YB1 SL7207 (aroA gene deletion), VNP20009 (∆msbB/∆purI) and ΔppGpp (PTet and PBAD), and Listeria monocytogenes Lmat-LLO have been developed to combat cancer cells. When used in tandem with conventional treatments, GEB substantially improve the efficacy of anticancer therapy outcomes. In addition, public acceptance, optimal timing (s), duration (s), dose (s), and strains identification, interactions with other strains and the host cells, efficacy, safety and quality, and potential risks and ethical dilemmas include major challenges.
Collapse
Affiliation(s)
- Zahra Zahedifard
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Shirin Mahmoodi
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Abdolmajid Ghasemian
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| |
Collapse
|
|
2
|
Shiozaki M, Kanno K, Yonezawa S, Otani Y, Shigenobu Y, Haratake D, Murakami E, Oka S, Ito M. Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159532. [PMID: 38981571 DOI: 10.1016/j.bbalip.2024.159532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/21/2024] [Accepted: 07/05/2024] [Indexed: 07/11/2024]
Abstract
Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r2 = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.
Collapse
Affiliation(s)
- Minami Shiozaki
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Keishi Kanno
- Department of General Internal Medicine, Hiroshima University Hospital, Japan.
| | - Sayaka Yonezawa
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Yuichiro Otani
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Yuya Shigenobu
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Daisuke Haratake
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Masanori Ito
- Department of General Internal Medicine, Hiroshima University Hospital, Japan
| |
Collapse
|
|
3
|
Bartolomé RA, Casal JI. Proteomic profiling and network biology of colorectal cancer liver metastasis. Expert Rev Proteomics 2023; 20:357-370. [PMID: 37874121 DOI: 10.1080/14789450.2023.2275681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/23/2023] [Indexed: 10/25/2023]
Abstract
INTRODUCTION Tissue-based proteomic studies of colorectal cancer (CRC) metastasis have delivered fragmented results, with very few therapeutic targets and prognostic biomarkers moving beyond the discovery phase. This situation is likely due to the difficulties in obtaining and analyzing large numbers of patient-derived metastatic samples, the own heterogeneity of CRC, and technical limitations in proteomics discovery. As an alternative, metastatic CRC cell lines provide a flexible framework to investigate the underlying mechanisms and network biology of metastasis for target discovery. AREAS COVERED In this perspective, we comment on different in-depth proteomic studies of metastatic versus non-metastatic CRC cell lines. Identified metastasis-related proteins are introduced and discussed according to the spatial location in different cellular fractions, with special emphasis on membrane/adhesion proteins, secreted proteins, and nuclear factors, including miRNAs associated with liver metastasis. Moreover, we analyze the biological significance and potential therapeutic applications of the identified liver metastasis-related proteins. EXPERT OPINION The combination of protein discovery and functional analysis is the only way to accelerate the progress to clinical translation of the proteomic-derived findings in a relatively fast pace. Patient-derived organoids represent a promising alternative to patient tissues and cell lines, but further optimizations are still required for achieving solid and reproducible results.
Collapse
Affiliation(s)
- Rubén A Bartolomé
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain
| | - J Ignacio Casal
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain
| |
Collapse
|
|
4
|
Schultz CW, Nevler A. Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug. Biomedicines 2022; 10:3249. [PMID: 36552005 PMCID: PMC9775650 DOI: 10.3390/biomedicines10123249] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022] Open
Abstract
Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. Despite the overwhelming evidence demonstrating the efficacy of pyrvinium for the treatment of human cancers, pyrvinium has not yet been repurposed for the treatment of cancers. This review provides an in-depth analysis of the history of pyrvinium as a therapeutic, the rationale and data supporting its use as an anticancer agent, and the challenges associated with repurposing pyrvinium as an anti-cancer agent.
Collapse
Affiliation(s)
- Christopher W. Schultz
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Avinoam Nevler
- Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
5
|
Nalli M, Masci D, Urbani A, La Regina G, Silvestri R. Emerging Direct Targeting β-Catenin Agents. Molecules 2022; 27:molecules27227735. [PMID: 36431838 PMCID: PMC9698307 DOI: 10.3390/molecules27227735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
Aberrant accumulation of β-catenin in the cell nucleus as a result of deregulation of the Wnt/β-catenin pathway is found in various types of cancer. Direct β-catenin targeting agents are being researched despite obstacles; however, specific β-catenin drugs for clinical treatments have not been approved so far. We focused on direct β-catenin targeting of potential therapeutic value as anticancer agents. This review provides recent advances on small molecule β-catenin agents. Structure-activity relationships and biological activities of reported inhibitors are discussed. This work provides useful knowledge in the discovery of β-catenin agents.
Collapse
Affiliation(s)
- Marianna Nalli
- Laboratory Affiliated with the Institute Pasteur Italy—Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giuseppe La Regina
- Laboratory Affiliated with the Institute Pasteur Italy—Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Romano Silvestri
- Laboratory Affiliated with the Institute Pasteur Italy—Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Correspondence:
| |
Collapse
|
|
6
|
Lycopene protects against Bisphenol A induced toxicity on the submandibular salivary glands via the upregulation of PPAR-γ and modulation of Wnt/β-catenin signaling. Int Immunopharmacol 2022; 112:109293. [DOI: 10.1016/j.intimp.2022.109293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/20/2022] [Accepted: 09/25/2022] [Indexed: 11/13/2022]
|
|
7
|
Fan X, Chen J, Zhang Y, Wang S, Zhong W, Yuan H, Wu X, Wang C, Zheng Y, Wei Y, Xiao Y. Alpinetin promotes hair regeneration via activating hair follicle stem cells. Chin Med 2022; 17:63. [PMID: 35637486 PMCID: PMC9153166 DOI: 10.1186/s13020-022-00619-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Background Alopecia affects millions of individuals globally, with hair loss becoming more common among young people. Various traditional Chinese medicines (TCM) have been used clinically for treating alopecia, however, the effective compounds and underlying mechanism are less known. We sought to investigate the effect of Alpinetin (AP), a compound extracted from Fabaceae and Zingiberaceae herbs, in hair regeneration. Methods Animal model for hair regeneration was mimicked by depilation in C57BL/6J mice. The mice were then topically treated with 3 mg/ml AP, minoxidil as positive control (PC), or solvent ethanol as vehicle control (VC) on the dorsal skin. Skin color changes which reflected the hair growth stages were monitored and pictured, along with H&E staining and hair shaft length measurement. RNA-seq analysis combined with immunofluorescence staining and qPCR analysis were used for mechanism study. Meanwhile, Gli1CreERT2; R26RtdTomato and Lgr5EGFP−CreERT2; R26RtdTomato transgenic mice were used to monitor the activation and proliferation of Gli1+ and Lgr5+ HFSCs after treatment. Furthermore, the toxicity of AP was tested in keratinocytes and fibroblasts from both human and mouse skin to assess the safety. Results When compared to minoxidil-treated and vehicle-treated control mice, topical application of AP promoted anagen initiation and delayed catagen entry, resulting in a longer anagen phase and hair shaft length. Mechanistically, RNA-seq analysis combined with immunofluorescence staining of Lef1 suggested that Lgr5+ HFSCs in lower bulge were activated by AP via Wnt signaling. Other HFSCs, including K15+, Lef1+, and Gli1+ cells, were also promoted into proliferating upon AP treatment. In addition, AP inhibited cleaved caspase 3-dependent apoptosis at the late anagen stage to postpone regression of hair follicles. More importantly, AP showed no cytotoxicity in keratinocytes and fibroblasts from both human and mouse skin. Conclusion This study clarified the effect of AP in promoting hair regeneration by activating HFSCs via Wnt signaling. Our findings may contribute to the development of a new generation of pilatory that is more efficient and less cytotoxic for treating alopecia. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-022-00619-2.
Collapse
Affiliation(s)
- Xiaojiao Fan
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Jing Chen
- Zhejiang University - University of Edinburgh Institute, International Campus, Zhejiang University, Haining, Zhejiang, China.,Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yajun Zhang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Hangzhou, 310020, Zhejiang, China
| | - Siyi Wang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Hangzhou, 310020, Zhejiang, China
| | - Wenqian Zhong
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Huipu Yuan
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Hangzhou, 310020, Zhejiang, China
| | - Xia Wu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Hangzhou, 310020, Zhejiang, China
| | - Chaochen Wang
- Zhejiang University - University of Edinburgh Institute, International Campus, Zhejiang University, Haining, Zhejiang, China.,Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yixin Zheng
- Zhejiang University - University of Edinburgh Institute, International Campus, Zhejiang University, Haining, Zhejiang, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
| | - Ying Xiao
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Hangzhou, 310020, Zhejiang, China.
| |
Collapse
|
|
8
|
Vallée A. Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway. Int J Mol Sci 2022; 23:ijms23052810. [PMID: 35269952 PMCID: PMC8910888 DOI: 10.3390/ijms23052810] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a very complex syndrome involving widespread brain multi-dysconnectivity. Schizophrenia is marked by cognitive, behavioral, and emotional dysregulations. Recent studies suggest that inflammation in the central nervous system (CNS) and immune dysfunction could have a role in the pathogenesis of schizophrenia. This hypothesis is supported by immunogenetic evidence, and a higher incidence rate of autoimmune diseases in patients with schizophrenia. The dysregulation of the WNT/β-catenin pathway is associated with the involvement of neuroinflammation in schizophrenia. Several studies have shown that there is a vicious and positive interplay operating between neuroinflammation and oxidative stress. This interplay is modulated by WNT/β-catenin, which interacts with the NF-kB pathway; inflammatory factors (including IL-6, IL-8, TNF-α); factors of oxidative stress such as glutamate; and dopamine. Neuroinflammation is associated with increased levels of PPARγ. In schizophrenia, the expression of PPAR-γ is increased, whereas the WNT/β-catenin pathway and PPARα are downregulated. This suggests that a metabolic-inflammatory imbalance occurs in this disorder. Thus, this research’s triptych could be a novel therapeutic approach to counteract both neuroinflammation and oxidative stress in schizophrenia.
Collapse
Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation (DRCI), Foch Hospital, 92150 Suresnes, France
| |
Collapse
|
|
9
|
Wang KX, Du GH, Qin XM, Gao L. Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153781. [PMID: 34649212 DOI: 10.1016/j.phymed.2021.153781] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/14/2021] [Accepted: 09/25/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most extensive and most deadly cancers worldwide. The invasion and metastasis characteristics of HCC dramatically affect the prognosis and survival of HCC patients. Compound Kushen Injection (CKI) is a GMP produced, proverbially applied traditional Chinese medicine formula in China to treat cancer-associated pains, and used as an adjunctive therapy for HCC. Until so far, whether CKI could suppress the metastasis of HCC through regulation of epithelial-mesenchymal transition or metabolic reprogramming is still ambiguous. PURPOSE In this study, the anti-metastasis effects of CKI were clarified and its pharmacological mechanisms were systematically explored. METHODS Cell invasion and cell adhesion assay were performed in SMMC-7721 cells to assess the anti-metastasis role of CKI, and the histopathological evaluation and biochemical detection were utilized in DEN-induced HCC rats to verify the anti-HCC effect of CKI. Serum and liver samples were analyzed with 1H NMR metabolomics approach to screen the differential metabolites and further target quantification the content of key metabolites. Finally, western blotting and immunofluorescence assay were applied to verify the crucial signaling pathway involved in metabolites. RESULTS CKI markedly repressed the invasion and adhesion in SMMC-7721 cells and significantly improved the liver function of DEN-induced HCC rats. CKI significantly regulated the expression of epithelial-mesenchymal transition (EMT) markers (Vimentin and E-cadherin). Metabolomics results showed that CKI regulated the metabolic reprogramming of HCC by inhibiting the key metabolites (citrate and lactate) and enzymes (HK and PK) in glycolysis process. Importantly, we found that c-Myc mediates the inhibitory effect of CKI on glycolysis. We further demonstrated that CKI inhibits c-Myc expression through modulating Wnt/β-catenin pathway in SMMC-7721 cells and DEN-induced HCC rats. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of CKI on HCC were diminished. CONCLUSION Together, this study reveals that CKI intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling pathway. Our research provides a new understanding of the mechanism of CKI against invasion and metastasis of HCC from the perspective of metabolic reprogramming.
Collapse
Affiliation(s)
- Ke-Xin Wang
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China
| | - Guan-Hua Du
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China.
| | - Li Gao
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China.
| |
Collapse
|
|
10
|
Mao Y, Lv J, Jiang L, Wang Y. Integrative analysis of ceRNA network reveals functional lncRNAs associated with independent recurrent prognosis in colon adenocarcinoma. Cancer Cell Int 2021; 21:352. [PMID: 34225739 PMCID: PMC8259330 DOI: 10.1186/s12935-021-02069-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/29/2021] [Indexed: 01/10/2023] Open
Abstract
Background Long non-coding RNAs (lncRNAs), acting as competing endogenous RNA (ceRNA) have been reported to regulate the expression of targeted genes by sponging miRNA in colon adenocarcinoma (COAD). Methods However, their potential implications for recurrence free survival prognosis and functional roles remains largely unclear in COAD. In this study, we downloaded the TCGA dataset (training dataset) and GSE39582 (validation dataset) of COAD patients with prognostic information. Results A total of 411 differentially expressed genes (DElncRNAs: 12 downregulated and 43 upregulated), 18 DE miRNAs (9 downregulated and 9 upregulated) and 338 DEmRNAs (113 downregulated and 225 upregulated) were identified in recurrence samples compared with non-recurrence samples with the thresholds of FDR < 0.05 and |log2FC|> 0.263. Based on six signature lncRNAs (LINC00899, LINC01503, PRKAG2-AS1, RAD21-AS1, SRRM2-AS1 and USP30-AS1), the risk score (RS) system was constructed. Two prognostic clinical features, including pathologic stage and RS model status were screened for building the nomogram survival model. Moreover, a recurrent-specific ceRNA network was successfully constructed with 2 signature lncRNAs, 4 miRNAs and 113 mRNAs. Furthermore, we further manifested that SRRM2-AS1 predicted a poor prognosis in COAD patients. Furthermore, knockdown of SRRM2-AS1 significantly suppressed cell proliferation, migration, invasion and EMT markers in HT-29 and SW1116 cells. Conclusion These identified novel lncRNA signature and ceRNA network associated with recurrence prognosis might provide promising therapeutic targets for COAD patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02069-6.
Collapse
Affiliation(s)
- Yinling Mao
- Department of Abdominal Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang Province, China
| | - Jiachen Lv
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, NO. 150 Hapin Road, Harbin, 150001, Heilongjiang Province, China
| | - Li Jiang
- Department of Hemolymph, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang Province, China
| | - Yihui Wang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, NO. 150 Hapin Road, Harbin, 150001, Heilongjiang Province, China.
| |
Collapse
|
|
11
|
Abd El-Fadeal NM, Nafie MS, K. El-kherbetawy M, El-mistekawy A, Mohammad HMF, Elbahaie AM, Hashish AA, Alomar SY, Aloyouni SY, El-dosoky M, Morsy KM, Zaitone SA. Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/β-Catenin Signaling Inhibition. Int J Mol Sci 2021; 22:5213. [PMID: 34069111 PMCID: PMC8156814 DOI: 10.3390/ijms22105213] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 12/29/2022] Open
Abstract
In colon cancer, wingless (Wnt)/β-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/β-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and β-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/β-catenin/glycogen synthase kinase-3β (GSK-3β) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/β-catenin/GSK-3β signaling.
Collapse
Affiliation(s)
- Noha M. Abd El-Fadeal
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Mohamed S. Nafie
- Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt;
| | | | - Amr El-mistekawy
- Department of Internal Medicine, Gastroenterology Division, Faculty of Medicine, Al-azhar University, Cairo 11651, Egypt;
| | - Hala M. F. Mohammad
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
- Central Laboratory, Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Alaaeldeen M. Elbahaie
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Abdullah A. Hashish
- Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia;
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Suliman Y. Alomar
- Doping Research Chair, Department of Zoology, College of Science, King Saud University, Riyadh 11495, Saudi Arabia
| | - Sheka Yagub Aloyouni
- Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh 36285, Saudi Arabia;
| | - Mohamed El-dosoky
- Department of Neuroscience Technology, College of Applied Medical Sciences in Jubail, Imam Abdulrahman Bin Faisal University, Jubail 35816, Saudi Arabia;
| | - Khaled M. Morsy
- Department of Anesthesia Technology, College of Applied Medical Science in Jubail, Imam Abdulrahman Bin Faisal University, Jubail 35816, Saudi Arabia;
| | - Sawsan A. Zaitone
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 714, Saudi Arabia
| |
Collapse
|
|
12
|
Vallée A, Lecarpentier Y, Vallée JN. Interplay of Opposing Effects of the WNT/β-Catenin Pathway and PPARγ and Implications for SARS-CoV2 Treatment. Front Immunol 2021; 12:666693. [PMID: 33927728 PMCID: PMC8076593 DOI: 10.3389/fimmu.2021.666693] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has quickly reached pandemic proportions. Cytokine profiles observed in COVID-19 patients have revealed increased levels of IL-1β, IL-2, IL-6, and TNF-α and increased NF-κB pathway activity. Recent evidence has shown that the upregulation of the WNT/β-catenin pathway is associated with inflammation, resulting in a cytokine storm in ARDS (acute respire distress syndrome) and especially in COVID-19 patients. Several studies have shown that the WNT/β-catenin pathway interacts with PPARγ in an opposing interplay in numerous diseases. Furthermore, recent studies have highlighted the interesting role of PPARγ agonists as modulators of inflammatory and immunomodulatory drugs through the targeting of the cytokine storm in COVID-19 patients. SARS-CoV2 infection presents a decrease in the angiotensin-converting enzyme 2 (ACE2) associated with the upregulation of the WNT/β-catenin pathway. SARS-Cov2 may invade human organs besides the lungs through the expression of ACE2. Evidence has highlighted the fact that PPARγ agonists can increase ACE2 expression, suggesting a possible role for PPARγ agonists in the treatment of COVID-19. This review therefore focuses on the opposing interplay between the canonical WNT/β-catenin pathway and PPARγ in SARS-CoV2 infection and the potential beneficial role of PPARγ agonists in this context.
Collapse
Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, Suresnes, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Jean-Noël Vallée
- University Hospital Center (CHU) Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France.,Laboratory of Mathematics and Applications (LMA), Unité Mixte de Recherche (UMR) Centre National de la Recherche Scientifique (CNRS) 7348, University of Poitiers, Poitiers, France
| |
Collapse
|
|
13
|
Lei S, Chen J, Song C, Li J, Zuo A, Xu D, Li T, Guo Y. CTRP9 alleviates foam cells apoptosis by enhancing cholesterol efflux. Mol Cell Endocrinol 2021; 522:111138. [PMID: 33352225 DOI: 10.1016/j.mce.2020.111138] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 12/11/2020] [Accepted: 12/17/2020] [Indexed: 12/27/2022]
Abstract
The apoptosis of foam cells leads to instability of atherosclerotic plaques. This study was designed to explore the protective role of CTRP9 in foam cell apoptosis. In our experiment, CTRP9 alleviated foam cell apoptosis. Meanwhile, CTRP9 upregulated the expression of proteins important for cholesterol efflux, such as LXRα, CYP27A1, ABCG1 and ABCA1, and improved cholesterol efflux in foam cells. Moreover, CTRP9 inhibited Wnt3a and β-catenin expression and β-catenin nuclear translocation in foam cells. In addition, adenovirus overexpression of Wnt3a abolished the effect of CTRP9 on macrophage apoptosis. Mechanistically, the AMPK inhibitor abolished the effect of CTRP9 on foam cell apoptosis, and downregulation of AdipoR1 by siRNA abrogated the activation of AMPK and the effect of CTRP9 on foam cell apoptosis. We concluded that CTRP9 achieved these protective effects on foam cells through the AdipoR1/AMPK pathway.
Collapse
Affiliation(s)
- Shengyun Lei
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Jiying Chen
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Chengxiang Song
- Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Jun Li
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Anju Zuo
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Dan Xu
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Tingting Li
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China.
| | - Yuan Guo
- Department of General Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China.
| |
Collapse
|
|
14
|
Gomart A, Vallée A, Lecarpentier Y. Necrotizing Enterocolitis: LPS/TLR4-Induced Crosstalk Between Canonical TGF-β/Wnt/β-Catenin Pathways and PPARγ. Front Pediatr 2021; 9:713344. [PMID: 34712628 PMCID: PMC8547806 DOI: 10.3389/fped.2021.713344] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
Necrotizing enterocolitis (NEC) represents one of the major causes of morbidity and mortality in premature infants. Several recent studies, however, have contributed to a better understanding of the pathophysiology of this dreadful disease. Numerous intracellular pathways play a key role in NEC, namely: bacterial lipopolysaccharide (LPS), LPS toll-like receptor 4 (TLR4), canonical Wnt/β-catenin signaling and PPARγ. In a large number of pathologies, canonical Wnt/β-catenin signaling and PPARγ operate in opposition to one another, so that when one of the two pathways is overexpressed the other is downregulated and vice-versa. In NEC, activation of TLR4 by LPS leads to downregulation of the canonical Wnt/β-catenin signaling and upregulation of PPARγ. This review aims to shed light on the complex intracellular mechanisms involved in this pathophysiological profile by examining additional pathways such as the GSK-3β, NF-κB, TGF-β/Smads, and PI3K-Akt pathways.
Collapse
Affiliation(s)
- Alexia Gomart
- Département de Pédiatrie et Médecine de l'adolescent, Centre Hospitalier Intercommunal de Créteil, Créteil, France
| | - Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, Suresnes, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien, Meaux, France
| |
Collapse
|
|
15
|
Lei X, Jing J, Zhang M, Guan B, Dong Z, Wang C. Bioinformatic Identification of Hub Genes and Analysis of Prognostic Values in Colorectal Cancer. Nutr Cancer 2020; 73:2568-2578. [PMID: 33153324 DOI: 10.1080/01635581.2020.1841249] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/30/2020] [Accepted: 10/15/2020] [Indexed: 12/24/2022]
Abstract
The purpose of this study is to discover novel hub genes which are helpful for diagnosis, prognosis, and targeted therapy in colorectal cancer (CRC) by using bioinformatics analysis. GSE74602, GSE110225, and GSE113513 were extracted from the gene expression omnibus (GEO). Differentially expressed genes (DEGs) in expression profiles were identified by GEO2R. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the DEGs were carried out in the Database for Annotation, Visualization, and Integrated Discovery (DAVID). String database and cytoscape were used for building protein-protein interaction (PPI) network and module analysis. The UALCAN was used for in-depth analysis of data of CRC patients from The Cancer Genome Atlas (TCGA) to identify expression levels and overall survival rates of hub genes. The DEGs included 107 up-regulation genes and 232 down-regulation genes. Twenty-nine (29) hub genes and two significant modules were screened from PPI network. The expression levels of hub genes in TCGA were verified. Survival analysis curve indicated high expression of CCNA2, CCNB1, DLGAP5, were related to high survival rates, and low expression of TIMP1 were associated with high survival rates. These results suggest that DEGs may be the hub genes of CRC, and CCNA2, CCNB1, DLGAP5, TIMP1 may be the potential prognostic markers of CRC.
Collapse
Affiliation(s)
- Xinyi Lei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jing Jing
- Department of Endocrinology, Municipal Hospital, Qingdao, China
| | - Miao Zhang
- Department of Respiratory, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bingsheng Guan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhiyong Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| |
Collapse
|
|
16
|
Andersen CB, Runge Walther A, Pipó-Ollé E, Notabi MK, Juul S, Eriksen MH, Lovatt AL, Cowie R, Linnet J, Kobaek-Larsen M, El-Houri R, Andersen MØ, Hedegaard MAB, Christensen LP, Arnspang EC. Falcarindiol Purified From Carrots Leads to Elevated Levels of Lipid Droplets and Upregulation of Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Cellular Models. Front Pharmacol 2020; 11:565524. [PMID: 32982759 PMCID: PMC7485416 DOI: 10.3389/fphar.2020.565524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/12/2020] [Indexed: 12/22/2022] Open
Abstract
Falcarindiol (FaDOH) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae). FaDOH has been shown to activate PPARγ and to increase the expression of the cholesterol transporter ABCA1 in cells, both of which play an important role in lipid metabolism. Thus, a common mechanism of action of the anticancer and antidiabetic properties of FaDOH may be due to a possible effect on lipid metabolism. In this study, the effect of sub-toxic concentration (5 μM) of FaDOH inside human mesenchymal stem cells (hMSCs) was studied using white light microscopy and Raman imaging. Our results show that FaDOH increases lipid content in the hMSCs cells as well as the number of lipid droplets (LDs) and that this can be explained by increased expression of PPARγ2 as shown in human colon adenocarcinoma cells. Activation of PPARγ can lead to increased expression of ABCA1. We demonstrate that ABCA1 is upregulated in colorectal neoplastic rat tissue, which indicates a possible role of this transporter in the redistribution of lipids and increased formation of LDs in cancer cells that may lead to endoplasmic reticulum stress and cancer cell death.
Collapse
Affiliation(s)
- Camilla Bertel Andersen
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Anders Runge Walther
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark.,The Maersk Mc-Kinney Moller Institute, University of Southern Denmark, Odense, Denmark
| | - Emma Pipó-Ollé
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Martine K Notabi
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Sebastian Juul
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Mathias Hessellund Eriksen
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Adam Leslie Lovatt
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Richard Cowie
- The Maersk Mc-Kinney Moller Institute, University of Southern Denmark, Odense, Denmark
| | - Jes Linnet
- The Maersk Mc-Kinney Moller Institute, University of Southern Denmark, Odense, Denmark.,Mads Clausen Institute, University of Southern Denmark, Odense, Denmark
| | - Morten Kobaek-Larsen
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Surgery, Odense University Hospital, Odense, Denmark
| | - Rime El-Houri
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Morten Østergaard Andersen
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Martin Aage Barsøe Hedegaard
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| | - Lars Porskjær Christensen
- Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Esbjerg, Denmark
| | - Eva Christensen Arnspang
- Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
| |
Collapse
|
|
17
|
Liñares-Blanco J, Munteanu CR, Pazos A, Fernandez-Lozano C. Molecular docking and machine learning analysis of Abemaciclib in colon cancer. BMC Mol Cell Biol 2020; 21:52. [PMID: 32640984 PMCID: PMC7346626 DOI: 10.1186/s12860-020-00295-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/24/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The main challenge in cancer research is the identification of different omic variables that present a prognostic value and personalised diagnosis for each tumour. The fact that the diagnosis is personalised opens the doors to the design and discovery of new specific treatments for each patient. In this context, this work offers new ways to reuse existing databases and work to create added value in research. Three published signatures with significante prognostic value in Colon Adenocarcinoma (COAD) were indentified. These signatures were combined in a new meta-signature and validated with main Machine Learning (ML) and conventional statistical techniques. In addition, a drug repurposing experiment was carried out through Molecular Docking (MD) methodology in order to identify new potential treatments in COAD. RESULTS The prognostic potential of the signature was validated by means of ML algorithms and differential gene expression analysis. The results obtained supported the possibility that this meta-signature could harbor genes of interest for the prognosis and treatment of COAD. We studied drug repurposing following a molecular docking (MD) analysis, where the different protein data bank (PDB) structures of the genes of the meta-signature (in total 155) were confronted with 81 anti-cancer drugs approved by the FDA. We observed four interactions of interest: GLTP - Nilotinib, PTPRN - Venetoclax, VEGFA - Venetoclax and FABP6 - Abemaciclib. The FABP6 gene and its role within different metabolic pathways were studied in tumour and normal tissue and we observed the capability of the FABP6 gene to be a therapeutic target. Our in silico results showed a significant specificity of the union of the protein products of the FABP6 gene as well as the known action of Abemaciclib as an inhibitor of the CDK4/6 protein and therefore, of the cell cycle. CONCLUSIONS The results of our ML and differential expression experiments have first shown the FABP6 gene as a possible new cancer biomarker due to its specificity in colonic tumour tissue and no expression in healthy adjacent tissue. Next, the MD analysis showed that the drug Abemaciclib characteristic affinity for the different protein structures of the FABP6 gene. Therefore, in silico experiments have shown a new opportunity that should be validated experimentally, thus helping to reduce the cost and speed of drug screening. For these reasons, we propose the validation of the drug Abemaciclib for the treatment of colon cancer.
Collapse
Affiliation(s)
- Jose Liñares-Blanco
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain
| | - Cristian R Munteanu
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain.,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain
| | - Alejandro Pazos
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain.,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain
| | - Carlos Fernandez-Lozano
- Department of Computer Science and Information Technologies, Faculty of Computer Science, University of A Coruña, CITIC, Campus Elviña s/n, A Coruña, 15071, Spain. .,Grupo de Redes de Neuronas Artificiales y Sistemas Adaptativos. Imagen Médica y Diagnóstico Radiológico (RNASA-IMEDIR). Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), Xubias de arriba, 84, A Coruña, 15006, Spain.
| |
Collapse
|
|
18
|
Sidrat T, Khan AA, Idrees M, Joo MD, Xu L, Lee KL, Kong IK. Role of Wnt Signaling During In-Vitro Bovine Blastocyst Development and Maturation in Synergism with PPARδ Signaling. Cells 2020; 9:cells9040923. [PMID: 32283810 PMCID: PMC7226827 DOI: 10.3390/cells9040923] [Citation(s) in RCA: 13] [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: 03/09/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
Wnt/β-catenin signaling plays vital role in the regulation of cellular proliferation, migration, stem cells cell renewal and genetic stability. This pathway is crucial during the early developmental process; however, the distinct role of Wnt/β-catenin signaling during pre-implantation period of bovine embryonic development is obscure. Here, we evaluated the critical role of Wnt/β-catenin pathway in the regulation of bovine blastocyst (BL) development and hatching. 6 bromoindurbin-3’oxime (6-Bio) was used to stimulate the Wnt signaling. Treatment with 6-Bio induced the expression of peroxisome proliferator-activated receptor-delta (PPARδ). Interestingly, the PPARδ co-localized with β-catenin and form a complex with TCF/LEF transcription factor. This complex potentiated the expression of several Wnt directed genes, which regulate early embryonic development. Inhibition of PPARδ with selective inhibitor 4-chloro-N-(2-{[5-trifluoromethyl]-2-pyridyl]sulfonyl}ethyl)benzamide (Gsk3787) severely perturbed the BL formation and hatching. The addition of Wnt agonist successfully rescued the BL formation and hatching ability. Importantly, the activation of PPARδ expression by Wnt stimulation enhanced cell proliferation and fatty acid oxidation (FAO) metabolism to improve BL development and hatching. In conclusion, our study provides the evidence that Wnt induced PPARδ expression co-localizes with β-catenin and is a likely candidate of canonical Wnt pathway for the regulation of bovine embryonic development.
Collapse
Affiliation(s)
- Tabinda Sidrat
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
| | - Abdul Aziz Khan
- Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ 07110, USA;
| | - Muhammad Idrees
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
| | - Myeong-Don Joo
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
| | - Lianguang Xu
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
| | - Kyeong-Lim Lee
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
| | - Il-Keun Kong
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea; (T.S.); (M.I.); (L.X.)
- Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea
- Correspondence: ; Tel.: +82-55-772-1942
| |
Collapse
|
|
19
|
Wang Y, Nakajima T, Gonzalez FJ, Tanaka N. PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice. Int J Mol Sci 2020; 21:2061. [PMID: 32192216 PMCID: PMC7139552 DOI: 10.3390/ijms21062061] [Citation(s) in RCA: 322] [Impact Index Per Article: 64.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/09/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022] Open
Abstract
Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.
Collapse
Affiliation(s)
- Yaping Wang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (Y.W.); (T.N.)
| | - Takero Nakajima
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (Y.W.); (T.N.)
| | - Frank J. Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (Y.W.); (T.N.)
- Research Center for Social Systems, Shinshu University, Matsumoto, Nagano 390-8621, Japan
| |
Collapse
|
|
20
|
Yang H, Lin HC, Liu H, Gan D, Jin W, Cui C, Yan Y, Qian Y, Han C, Wang Z. A 6 lncRNA-Based Risk Score System for Predicting the Recurrence of Colon Adenocarcinoma Patients. Front Oncol 2020; 10:81. [PMID: 32117736 PMCID: PMC7015976 DOI: 10.3389/fonc.2020.00081] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Colon adenocarcinoma (COAD) is a common type of colon cancer, and post-operative recurrence and metastasis may occur in COAD patients. This study is designed to build a risk score system for COAD patients. The Cancer Genome Atlas (TCGA) dataset of COAD (the training set) was downloaded, and GSE17538 and GSE39582 (the validation sets) from Gene Expression Omnibus database were obtained. The differentially expressed RNAs (DERs) were analyzed by limma package. Using survival package, the independent prognosis-associated long non-coding RNAs (lncRNAs) were selected for constructing risk score system. After the independent clinical prognostic factors were screened out using survival package, a nomogram survival model was constructed using rms package. Furthermore, competitive endogenous RNA (ceRNA) regulatory network and enrichment analyses separately were performed using Cytoscape software and DAVID tool. Totally 404 DERs between recurrence and non-recurrence groups were identified. Based on the six independent prognosis-associated lncRNAs (including H19, KCNJ2-AS1, LINC00899, LINC01503, PRKAG2-AS1, and SRRM2-AS1), the risk score system was constructed. After the independent clinical prognostic factors (Pathologic M, pathologic T, and RS model status) were identified, the nomogram survival model was built. In the ceRNA regulatory network, there were three lncRNAs, four miRNAs, and 77 mRNAs. Additionally, PPAR signaling pathway and hedgehog signaling pathway were enriched for the mRNAs in the ceRNA regulatory network. The risk score system and the nomogram survival model might be used for predicting COAD recurrence. Besides, PPAR signaling pathway and hedgehog signaling pathway might affect the recurrence of COAD patients.
Collapse
Affiliation(s)
- Haojie Yang
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong-Cheng Lin
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University (Gastrointestinal & Anal Hospital of Sun Yat-sen University), Guangzhou, China
| | - Hua Liu
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Gan
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Jin
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Can Cui
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yixin Yan
- Department of Emergency Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Qian
- Department of Emergency Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Changpeng Han
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenyi Wang
- Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
21
|
Seetha A, Devaraj H, Sudhandiran G. Indomethacin and juglone inhibit inflammatory molecules to induce apoptosis in colon cancer cells. J Biochem Mol Toxicol 2020; 34:e22433. [PMID: 31916655 DOI: 10.1002/jbt.22433] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/13/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is the third most common fatal cancer. Indomethacin, a nonsteroidal anti-inflammatory drug, is known to reduce the occurrence of CRC. This study evaluated the potential anticolon cancer effects of juglone (5-hydroxy-1,4-naphthoquinone) in combination with indomethacin. Human colon adenocarcinoma cells (HT29) were subjected to treatment with indomethacin, juglone, and a combination of both. Morphological analysis, cell cycle regulation, and dual staining using acridine orange and ethidium bromide in control and treated cells revealed the apoptotic potential of these compounds. Bcl2 and inflammatory molecules (tumor necrosis factor-α, nuclear factor kappa B, and Cox-2) were found to be decreased with a concomitant increase in the expression of proapoptotic molecules (Bad, Bax, cytochrome c, and PUMA) as a result of the molecular regulation of Wnt, Notch, and peroxisome proliferator-activated receptor-γ signaling. Treatment with juglone was not as effective as with indomethacin; however, a combination of both was shown to be more effective, suggesting that juglone may be considered for therapeutic intervention of colon cancer.
Collapse
Affiliation(s)
- Alagesan Seetha
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
| | - Halagowder Devaraj
- Department of Zoology, University of Madras, Guindy Campus, Chennai, India
| | | |
Collapse
|
|
22
|
Bao Z, Zhu Y, Ge Q, Gu W, Dong X, Bai Y. Signaling Pathway Analysis Combined With the Strength Variations of Interactions Between Genes Under Different Conditions. IEEE ACCESS 2020; 8:138036-138045. [DOI: 10.1109/access.2020.3010796] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
23
|
Liu D, Yu H, Zhang Q. Dietary vitamin E regulates the activity of antioxidant enzymes through Wnt10b signaling in the muscle of zebrafish. Food Funct 2020; 11:10665-10674. [DOI: 10.1039/d0fo02083d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Vitamin E (VE) regulates the activity of antioxidant enzymes through Wnt10b signaling in zebrafish.
Collapse
Affiliation(s)
- Dongwu Liu
- School of Agricultural Engineering and Food Science
- Shandong University of Technology
- Zibo 255049
- China
- State Key Laboratory of Food Science and Technology
| | - Hairui Yu
- College of Biological and Agricultural Engineering
- Weifang Bioengineering Technology Research Center
- Weifang University
- Weifang 261061
- China
| | - Qin Zhang
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications
- Guangxi Colleges and Universities Key Laboratory of Utilization of Microbial and Botanical Resources
- School of Marine Science and Biotechnology
- Guangxi University for Nationalities
- Nanning 530008
| |
Collapse
|
|
24
|
Xiong X, Schober M, Tassone E, Khodadadi-Jamayran A, Sastre-Perona A, Zhou H, Tsirigos A, Shen S, Chang M, Melamed J, Ossowski L, Wilson EL. KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer. Cell Rep 2019; 25:3006-3020.e7. [PMID: 30540935 PMCID: PMC6405286 DOI: 10.1016/j.celrep.2018.11.065] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 11/07/2018] [Accepted: 11/15/2018] [Indexed: 12/18/2022] Open
Abstract
There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that
genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such
gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and
controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts
PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic
analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent
tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced
cancer. Available criteria for segregating prostate cancer patients into those requiring therapeutic intervention and those who can
be followed are inadequate. Xiong et al. show that KLF4 and its downstream targets make up a gene signature that identifies
indolent tumors. This approach may improve prognosis and identify therapeutic targets for advanced cancer.
Collapse
Affiliation(s)
- Xiaozhong Xiong
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
| | - Markus Schober
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Department of Dermatology, NYU School of Medicine, New York, NY 10016, USA
| | - Evelyne Tassone
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA
| | - Alireza Khodadadi-Jamayran
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY 10016, USA
| | - Ana Sastre-Perona
- Department of Dermatology, NYU School of Medicine, New York, NY 10016, USA
| | - Hua Zhou
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY 10016, USA
| | - Aristotelis Tsirigos
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY 10016, USA
| | - Steven Shen
- Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Miao Chang
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA
| | - Jonathan Melamed
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Liliana Ossowski
- Department of Medicine, Mt. Sinai School of Medicine, New York, NY 10029, USA
| | - Elaine L Wilson
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Department of Urology, NYU School of Medicine, New York, NY 10016, USA.
| |
Collapse
|
|
25
|
Khan FU, Owusu-Tieku NYG, Dai X, Liu K, Wu Y, Tsai HI, Chen H, Sun C, Huang L. Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin. Front Pharmacol 2019; 10:1308. [PMID: 31824307 PMCID: PMC6886402 DOI: 10.3389/fphar.2019.01308] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 10/15/2019] [Indexed: 01/08/2023] Open
Abstract
Emerging evidence suggests that fibromodulin (FMOD), an extracellular matrix protein, is associated with cancer, and yet little is known about the regulation of FMOD expression and its role in cancer metastasis. Aspirin, a classic anti-inflammatory drug, has been indicated to offer anticancer benefits, but its action targets and mechanisms remain obscure. In the present study using cell lines, animal model and database analysis, we show that FMOD is crucial for breast cancer cell migration and invasion (BCCMI) via activation of ERK; expression of FMOD is regulated positively by the Wnt/β-catenin pathway, wherein the β-catenin/TCF4/LEF1 complex binds the FMOD promoter to transcribe FMOD. Aspirin inhibits BCCMI by attenuating Wnt/β-catenin signaling and suppressing FMOD expression via inhibiting deacetylation of β-catenin by histone deacetylase 6 (HDAC6) leading to β-catenin phosphorylation and cytoplasmic degradation. Moreover, expression of the transcriptional complex components β-catenin/TCF4/LEF1 is upregulated by the Wnt/β-catenin pathway, constituting positive feedback loops that amplify its signal output. Our findings identify a critical role of FMOD in cancer metastasis, reveal a mechanism regulating FMOD transcription and impacting tumor metastasis, uncover action targets and mechanism for the anticancer activity of Aspirin, and expand the understanding of the Wnt/β-catenin pathway and tumor metastasis, which are valuable for development of cancer therapeutics.
Collapse
Affiliation(s)
- Fahim Ullah Khan
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Nana Yaa Gyaama Owusu-Tieku
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, China
| | - Xiaoyong Dai
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, China
| | - Kewei Liu
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Yanping Wu
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Hsiang-I Tsai
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Hongbo Chen
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Chunhui Sun
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, China
| | - Laiqiang Huang
- School of Life Sciences, Tsinghua University, Beijing, China.,Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology (prep), Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China.,Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, China
| |
Collapse
|
|
26
|
Kim JT, Li C, Weiss HL, Zhou Y, Liu C, Wang Q, Evers BM. Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells. Cells 2019; 8:cells8091106. [PMID: 31546785 PMCID: PMC6770209 DOI: 10.3390/cells8091106] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/10/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
The Wnt/β-catenin pathway plays a crucial role in development and renewal of the intestinal epithelium. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme in the synthesis of ketone body β-hydroxybutyrate (βHB), contributes to the regulation of intestinal cell differentiation. Here, we have shown that HMGCS2 is a novel target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cancer cell lines and normal intestinal organoids. Inhibition of the Wnt/β-catenin pathway resulted in increased protein and mRNA expression of HMGCS2 and βHB production in human colon cancer cell lines LS174T and Caco2. In addition, Wnt inhibition increased expression of PPARγ and its target genes, FABP2 and PLIN2, in these cells. Conversely, activation of Wnt/β-catenin signaling decreased protein and mRNA levels of HMGCS2, βHB production, and expression of PPARγ and its target genes in LS174T and Caco2 cells and mouse intestinal organoids. Moreover, inhibition of PPARγ reduced HMGCS2 expression and βHB production, while activation of PPARγ increased HMGCS2 expression and βHB synthesis. Furthermore, PPARγ bound the promoter of HMGCS2 and this binding was enhanced by β-catenin knockdown. Finally, we showed that HMGCS2 inhibited, while Wnt/β-catenin stimulated, glycolysis, which contributed to regulation of intestinal cell differentiation. Our results identified HMGCS2 as a downstream target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cells. Moreover, our findings suggest that Wnt/β-catenin/PPARγ signaling regulates intestinal cell differentiation, at least in part, through regulation of ketogenesis.
Collapse
Affiliation(s)
- Ji Tae Kim
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
| | - Chang Li
- Department of Surgery, University of Kentucky, Lexington, KY 40536 USA.
| | - Heidi L Weiss
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
| | - Yuning Zhou
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
| | - Chunming Liu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
| | - Qingding Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
- Department of Surgery, University of Kentucky, Lexington, KY 40536 USA.
| | - B Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA.
- Department of Surgery, University of Kentucky, Lexington, KY 40536 USA.
| |
Collapse
|
|
27
|
Zhou P, Zhang X, Guo M, Guo R, Wang L, Zhang Z, Lin Z, Dong M, Dai H, Ji X, Lu H. Ginsenoside Rb1 ameliorates CKD-associated vascular calcification by inhibiting the Wnt/β-catenin pathway. J Cell Mol Med 2019; 23:7088-7098. [PMID: 31423730 PMCID: PMC6787443 DOI: 10.1111/jcmm.14611] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/14/2019] [Accepted: 08/08/2019] [Indexed: 01/04/2023] Open
Abstract
Vascular calcification (VC) is a pathological process underpinning major cardiovascular conditions and has attracted public attention due to its high morbidity and mortality. Chronic kidney disease (CKD) is a common disease related to VC. Ginsenoside Rb1 (Rb1) has been reported to protect the cardiovascular system against vascular diseases, yet its role in VC and the underlying mechanisms remain unclear. In this study, we established a CKD‐associated VC rat model and a β‐glycerophosphate (β‐GP)‐induced vascular smooth muscle cell (VSMC) calcification model to investigate the effects of Rb1 on VC. Our results demonstrated that Rb1 ameliorated calcium deposition and VSMC osteogenic transdifferentiation both in vivo and in vitro. Rb1 treatment inhibited the Wnt/β‐catenin pathway by activating peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), and confocal microscopy was used to show that Rb1 inhibited β‐catenin nuclear translocation in VSMCs. Furthermore, SKL2001, an agonist of the Wnt/β‐catenin pathway, compromised the vascular protective effect of Rb1. GW9662, a PPAR‐γ antagonist, reversed Rb1's inhibitory effect on β‐catenin. These results indicate that Rb1 exerted anticalcific properties through PPAR‐γ/Wnt/β‐catenin axis, which provides new insights into the potential theraputics of VC.
Collapse
Affiliation(s)
- Peng Zhou
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xinyu Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Mengqi Guo
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Rong Guo
- Department of Cardiology, Ji'an Municipal Center People's Hospital, Ji'an, China
| | - Lei Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zihao Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zongwei Lin
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Mei Dong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Hongyan Dai
- Department of Cardiology, Qingdao Municipal Hospital, Qingdao, China
| | - Xiaoping Ji
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Huixia Lu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| |
Collapse
|
|
28
|
Chen JJ, Xiao ZJ, Meng X, Wang Y, Yu MK, Huang WQ, Sun X, Chen H, Duan YG, Jiang X, Wong MP, Chan HC, Zou F, Ruan YC. MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Am J Cancer Res 2019; 9:5049-5064. [PMID: 31410201 PMCID: PMC6691374 DOI: 10.7150/thno.32097] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 05/08/2019] [Indexed: 12/13/2022] Open
Abstract
Rationale: Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/β-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism. Methods: Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo. Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability. Wnt/β-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array. Normal and endometriotic human endometrial tissues were examined. Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed. In vitro and in vivo tumorigenesis was performed. Results: MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells. MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion: A previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality.
Collapse
|
|
29
|
Vallée A, Vallée JN, Lecarpentier Y. Metabolic reprogramming in atherosclerosis: Opposed interplay between the canonical WNT/β-catenin pathway and PPARγ. J Mol Cell Cardiol 2019; 133:36-46. [PMID: 31153873 DOI: 10.1016/j.yjmcc.2019.05.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/27/2019] [Accepted: 05/29/2019] [Indexed: 01/08/2023]
Abstract
Atherosclerosis, a chronic inflammatory and age-related disease, is a complex mechanism presenting a dysregulation of vessel structures. During this process, the canonical WNT/β-catenin pathway is increased whereas PPARγ is downregulated. The two systems act in an opposite manner. This paper reviews the opposing interplay of these systems and their metabolic-reprogramming pathway in atherosclerosis. Activation of the WNT/β-catenin pathway enhances the transcription of targets involved in inflammation, endothelial dysfunction, the proliferation of vascular smooth muscle cells, and vascular calcification. This complex mechanism, which is partly controlled by the WNT/β-catenin pathway, presents several metabolic dysfunctions. This phenomenon, called aerobic glycolysis (or the Warburg effect), consists of a shift in ATP production from mitochondrial oxidative phosphorylation to aerobic glycolysis, leading to the overproduction of intracellular lactate. This mechanism is partially due to the injury of mitochondrial respiration and an increase in the glycolytic pathway. In contrast, PPARγ agonists downregulate the WNT/β-catenin pathway. Therefore, the development of therapeutic targets, such as PPARγ agonists, for the treatment of atherosclerosis could be an interesting and innovative way of counteracting the canonical WNT pathway.
Collapse
Affiliation(s)
- Alexandre Vallée
- Diagnosis and Therapeutic Center, Hypertension and Cardiovascular Prevention Unit, Hotel-Dieu Hospital, AP-HP, Université Paris Descartes, Paris, France.
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80054 Amiens, France; Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 6-8 rue Saint-fiacre, 77100 Meaux, France
| |
Collapse
|
|
30
|
Vallée A, Vallée JN, Lecarpentier Y. PPARγ agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/β-catenin pathway. Mol Psychiatry 2019; 24:643-652. [PMID: 30104725 DOI: 10.1038/s41380-018-0131-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/24/2018] [Accepted: 06/08/2018] [Indexed: 12/13/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/β-catenin pathway is one of the major pathways involved. The canonical WNT/β-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) act in an opposed manner. In ASD, the canonical WNT/β-catenin pathway is increased while PPARγ seems to be decreased. PPARγ agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/β-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARγ and the canonical WNT/β-catenin pathway in ASD and the potential role of PPARγ agonists as treatment for ASD.
Collapse
Affiliation(s)
- Alexandre Vallée
- Paris-Descartes University; Diagnosis and Therapeutic Center, Hôtel-Dieu Hospital; AP-HP, Paris, France. .,Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France.
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80054, Amiens, France.,Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 6-8 rue Saint-fiacre, 77100, Meaux, France
| |
Collapse
|
|
31
|
Bao Z, Zhu Y, Ge Q, Gu W, Dong X, Bai Y. gwSPIA: Improved Signaling Pathway Impact Analysis With Gene Weights. IEEE ACCESS 2019; 7:69172-69183. [DOI: 10.1109/access.2019.2918150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
32
|
Rhee JK, Kim SJ, Zhang BT. Identifying DNA Methylation Modules Associated with a Cancer by Probabilistic Evolutionary Learning. IEEE COMPUT INTELL M 2018. [DOI: 10.1109/mci.2018.2840659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
|
|
33
|
Orhan A, Gögenur I, Kissow H. The Intestinotrophic Effects of Glucagon-Like Peptide-2 in Relation to Intestinal Neoplasia. J Clin Endocrinol Metab 2018; 103:2827-2837. [PMID: 29741675 DOI: 10.1210/jc.2018-00655] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 05/01/2018] [Indexed: 02/07/2023]
Abstract
CONTEXT Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone with intestinotrophic and antiapoptotic effects. The hormone's therapeutic potential in intestinal diseases and relation to intestinal neoplasia has raised great interest among researchers. This article reviews and discusses published experimental and clinical studies concerning the growth-stimulating and antiapoptotic effects of GLP-2 in relation to intestinal neoplasia. EVIDENCE ACQUISITION The data used in this narrative review were collected through literature research in PubMed using English keywords. All studies to date examining GLP-2's relation to intestinal neoplasms have been reviewed in this article, as the studies on the matter are sparse. EVIDENCE SYNTHESIS GLP-2 has been found to stimulate intestinal growth through secondary mediators and through the involvement of Akt phosphorylation. Studies on rodents have shown that exogenously administered GLP-2 increases the growth and incidence of adenomas in the colon, suggesting that GLP-2 may play an important role in the progression of intestinal tumors. Clinical studies have found that exogenous GLP-2 treatment is well tolerated for up to 30 months, but the tolerability for even longer periods of treatment has not been examined. CONCLUSION Exogenous GLP-2 is currently available as teduglutide for the treatment of short bowel syndrome. However, the association between exogenous GLP-2 treatment and intestinal neoplasia in humans has not been fully identified. This leads to a cause for concern regarding the later risk of the development or progression of intestinal tumors with long-term GLP-2 treatment. Therefore, further research regarding GLP-2's potential relation to intestinal cancers is needed.
Collapse
Affiliation(s)
- Adile Orhan
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Koege, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
- NNF Center of Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| |
Collapse
|
|
34
|
The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells. Int J Mol Sci 2018; 19:ijms19071907. [PMID: 29966227 PMCID: PMC6073339 DOI: 10.3390/ijms19071907] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/10/2018] [Accepted: 06/24/2018] [Indexed: 12/13/2022] Open
Abstract
Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has been neglected for a long time. Meanwhile, over the past 20 years, a recovery of the study regarding cancer metabolism has led to an increasing consideration of metabolic alterations in tumors. Cancer cells must adapt their metabolism to meet their energetic and biosynthetic demands, which are associated with the rapid growth of the primary tumor and colonization of distinct metastatic sites. Cancer cells are largely dependent on aerobic glycolysis for their energy production, but are also associated with increased fatty acid synthesis and increased rates of glutamine consumption. In fact, emerging evidence has shown that therapeutic resistance to cancer treatment may arise from the deregulation of glucose metabolism, fatty acid synthesis, and glutamine consumption. Cancer cells exhibit a series of metabolic alterations induced by mutations that lead to a gain-of-function of oncogenes, and a loss-of-function of tumor suppressor genes, including increased glucose consumption, reduced mitochondrial respiration, an increase of reactive oxygen species, and cell death resistance; all of these are responsible for cancer progression. Cholesterol metabolism is also altered in cancer cells and supports uncontrolled cell growth. In this context, we discuss the roles of peroxisome proliferator-activated receptors (PPARs), which are master regulators of cellular energetic metabolism in the deregulation of the energetic homeostasis, which is observed in cancer. We highlight the different roles of PPAR isotypes and the differential control of their transcription in various cancer cells.
Collapse
|
|
35
|
Interplay between the renin-angiotensin system, the canonical WNT/β-catenin pathway and PPARγ in hypertension. Curr Hypertens Rep 2018; 20:62. [PMID: 29884931 DOI: 10.1007/s11906-018-0860-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Heterogeneous causes can determinate hypertension. RECENT FINDINGS The renin-angiotensin system (RAS) has a major role in the pathophysiology of blood pressure. Angiotensin II and aldosterone are overexpressed during hypertension and lead to hypertension development and its cardiovascular complications. In several tissues, the overactivation of the canonical WNT/β-catenin pathway leads to inactivation of peroxisome proliferator-activated receptor gamma (PPARγ), while PPARγ stimulation induces a decrease of the canonical WNT/β-catenin pathway. In hypertension, the WNT/β-catenin pathway is upregulated, whereas PPARγ is decreased. The WNT/β-catenin pathway and RAS regulate positively each other during hypertension, whereas PPARγ agonists can decrease the expression of both the WNT/β-catenin pathway and RAS. We focus this review on the hypothesis of an opposite interplay between PPARγ and both the canonical WNT/β-catenin pathway and RAS in regulating the molecular mechanism underlying hypertension. The interactions between PPARγ and the canonical WNT/β-catenin pathway through the regulation of the renin-angiotensin system in hypertension may be an interesting way to better understand the actions and the effects of PPARγ agonists as antihypertensive drugs.
Collapse
|
|
36
|
Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas. Neurosci Bull 2018; 34:573-588. [PMID: 29582250 PMCID: PMC5960455 DOI: 10.1007/s12264-018-0219-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 01/18/2018] [Indexed: 12/19/2022] Open
Abstract
In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.
Collapse
Affiliation(s)
- Alexandre Vallée
- Laboratory of Mathematics and Applications, Unités Mixtes de Recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348, University of Poitiers, Poitiers, France.
- Délégation à la Recherche Clinique et à l'Innovation (DRCI), Hôpital Foch, Suresnes, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien, Meaux, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France
| | - Jean-Noël Vallée
- Laboratory of Mathematics and Applications, Unités Mixtes de Recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348, University of Poitiers, Poitiers, France
- CHU Amiens Picardie, University of Picardie Jules Verne, Amiens, France
| |
Collapse
|
|
37
|
Vallée A, Vallée JN, Guillevin R, Lecarpentier Y. Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis. Cell Mol Neurobiol 2018; 38:783-795. [PMID: 28905149 PMCID: PMC11482031 DOI: 10.1007/s10571-017-0550-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/09/2017] [Indexed: 12/13/2022]
Abstract
Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.
Collapse
Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France.
| | - Jean-Noël Vallée
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France
- CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| |
Collapse
|
|
38
|
Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches. Int J Mol Sci 2018; 19:ijms19041212. [PMID: 29659554 PMCID: PMC5979570 DOI: 10.3390/ijms19041212] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 12/20/2022] Open
Abstract
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.
Collapse
Affiliation(s)
- Alexandre Vallée
- Délégation à la Recherche Clinique et à l'Innovation (DRCI), Hôpital Foch, 92150 Suresnes, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 77100 Meaux, France.
| | - Rémy Guillevin
- Data Analysis and Computations Through Imaging Modeling-Mathématiques (DACTIM), Unité mixte de recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348 (Laboratoire de Mathématiques et Application), University of Poitiers, Centre Hospitalier Universitaire (CHU) de Poitiers, 86000 Poitiers, France.
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, University of Picardie Jules Verne (UPJV), 80000 Amiens, France.
- LMA (Laboratoire de Mathématiques et Applications), Unité mixte de recherche (UMR), Centre National de la Recherche Scientifique (CNRS) 7348, Université de Poitiers, 86000 Poitiers, France.
| |
Collapse
|
|
39
|
Vallée A, Lecarpentier Y. Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. Front Immunol 2018; 9:745. [PMID: 29706964 PMCID: PMC5908886 DOI: 10.3389/fimmu.2018.00745] [Citation(s) in RCA: 274] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 03/26/2018] [Indexed: 12/19/2022] Open
Abstract
Inflammation and oxidative stress are common and co-substantial pathological processes accompanying, promoting, and even initiating numerous cancers. The canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) generally work in opposition. If one of them is upregulated, the other one is downregulated and vice versa. WNT/β-catenin signaling is upregulated in inflammatory processes and oxidative stress and in many cancers, although there are some exceptions for cancers. The opposite is observed with PPARγ, which is generally downregulated during inflammation and oxidative stress and in many cancers. This helps to explain in part the opposite and unidirectional profile of the canonical WNT/β-catenin signaling and PPARγ in these three frequent and morbid processes that potentiate each other and create a vicious circle. Many intracellular pathways commonly involved downstream will help maintain and amplify inflammation, oxidative stress, and cancer. Thus, many WNT/β-catenin target genes such as c-Myc, cyclin D1, and HIF-1α are involved in the development of cancers. Nuclear factor-kappaB (NFκB) can activate many inflammatory factors such as TNF-α, TGF-β, interleukin-6 (IL-6), IL-8, MMP, vascular endothelial growth factor, COX2, Bcl2, and inducible nitric oxide synthase. These factors are often associated with cancerous processes and may even promote them. Reactive oxygen species (ROS), generated by cellular alterations, stimulate the production of inflammatory factors such as NFκB, signal transducer and activator transcription, activator protein-1, and HIF-α. NFκB inhibits glycogen synthase kinase-3β (GSK-3β) and therefore activates the canonical WNT pathway. ROS activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling in many cancers. PI3K/Akt also inhibits GSK-3β. Many gene mutations of the canonical WNT/β-catenin pathway giving rise to cancers have been reported (CTNNB1, AXIN, APC). Conversely, a significant reduction in the expression of PPARγ has been observed in many cancers. Moreover, PPARγ agonists promote cell cycle arrest, cell differentiation, and apoptosis and reduce inflammation, angiogenesis, oxidative stress, cell proliferation, invasion, and cell migration. All these complex and opposing interactions between the canonical WNT/β-catenin pathway and PPARγ appear to be fairly common in inflammation, oxidative stress, and cancers.
Collapse
Affiliation(s)
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| |
Collapse
|
|
40
|
Zhao F, Xiao C, Evans KS, Theivanthiran T, DeVito N, Holtzhausen A, Liu J, Liu X, Boczkowski D, Nair S, Locasale JW, Hanks BA. Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization. Immunity 2018; 48:147-160.e7. [PMID: 29343435 PMCID: PMC5777287 DOI: 10.1016/j.immuni.2017.12.004] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 10/13/2017] [Accepted: 12/04/2017] [Indexed: 02/02/2023]
Abstract
Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.
Collapse
Affiliation(s)
- Fei Zhao
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA
| | - Christine Xiao
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA
| | - Kathy S Evans
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA
| | | | - Nicholas DeVito
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA
| | - Alisha Holtzhausen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Juan Liu
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| | - Xiaojing Liu
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| | - David Boczkowski
- Department of Surgery, Division of Surgical Sciences, Duke Cancer Institute, Durham, NC 27710, USA
| | - Smita Nair
- Department of Surgery, Division of Surgical Sciences, Duke Cancer Institute, Durham, NC 27710, USA
| | - Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| | - Brent A Hanks
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, NC 27710, USA.
| |
Collapse
|
|
41
|
Is the Wnt/β-catenin pathway involved in the anti-inflammatory activity of glucocorticoids in spinal cord injury? Neuroreport 2018; 27:1086-94. [PMID: 27513198 DOI: 10.1097/wnr.0000000000000663] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The Wnt canonical or the Wnt/β-catenin pathway has been implicated in the regulation of several physiopathological pathways such as inflammation. Glucocorticoids (GCs) are administered widely to treat inflammation in several diseases, including spinal cord injury (SCI). The aim of this study was to evaluate whether the Wnt canonical pathway is involved in experimental SCI and whether it is implicated in the anti-inflammatory activity of two different GCs: the methylprednisolone sodium succinate (MPSS), considered the standard treatment for acute SCI, and mometasone furoate (MF), mainly administered for the treatment of airway and skin diseases. Experimental SCI was induced in mice by surgical spinal cord compression at the T6-T7 level. Then, mice were treated with MPSS (6 mg/kg) or MF (0.1 mg/kg) for 7 days until they were killed. Both GCs were found to modulate the Wnt canonical pathway, but in particular, the MF treatment was shown to restore completely the downregulated pathway in SCI. The MF treatment also significantly increased peroxisome proliferator-activated receptor-γ, a Wnt target gene with anti-inflammatory properties, compared with MPSS, and it also inhibited the levels of the proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. Here, we suggest that MF has more efficacy than MPSS in inhibiting inflammation in an SCI experimental model and we propose the β-catenin/peroxisome proliferator-activated receptor-γ axis as the mechanism by which MF exerts these beneficial effects.
Collapse
|
|
42
|
Torres S, García-Palmero I, Marín-Vicente C, Bartolomé RA, Calviño E, Fernández-Aceñero MJ, Casal JI. Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer. J Proteome Res 2018; 17:252-264. [PMID: 29131639 DOI: 10.1021/acs.jproteome.7b00548] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We investigated new transcription and splicing factors associated with the metastatic phenotype in colorectal cancer. A concatenated tandem array of consensus transcription factor (TF)-response elements was used to pull down nuclear extracts in two different pairs of colorectal cancer cells, KM12SM/KM12C and SW620/480, genetically related but differing in metastatic ability. Proteins were analyzed by label-free LC-MS and quantified with MaxLFQ. We found 240 proteins showing a significant dysregulation in highly metastatic KM12SM cells relative to nonmetastatic KM12C cells and 257 proteins in metastatic SW620 versus SW480. In both cell lines there were similar alterations in genuine TFs and components of the splicing machinery like UPF1, TCF7L2/TCF-4, YBX1, or SRSF3. However, a significant number of alterations were cell-line specific. Functional silencing of MAFG, TFE3, TCF7L2/TCF-4, and SRSF3 in KM12 cells caused alterations in adhesion, survival, proliferation, migration, and liver homing, supporting their role in metastasis. Finally, we investigated the prognostic value of the altered TFs and splicing factors in cancer patients. SRSF3 and SFPQ showed significant prognostic value. We observed that SRSF3 displayed a gradual loss of expression associated with cancer progression. Loss of SRSF3 expression was significantly associated with poor survival and shorter disease-free survival, particularly in early stages, in colorectal cancer.
Collapse
Affiliation(s)
- Sofía Torres
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
| | - Irene García-Palmero
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
| | - Consuelo Marín-Vicente
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
- Proteomic Facilities, CIB-CSIC , Madrid 28040, Spain
| | - Rubén A Bartolomé
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
| | - Eva Calviño
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
| | | | - J Ignacio Casal
- Functional Proteomics, Centro de Investigaciones Biológicas (CIB-CSIC) , Ramiro de Maeztu 9, Madrid 28040, Spain
| |
Collapse
|
|
43
|
Albuquerque C, Pebre Pereira L. Wnt Signalling-Targeted Therapy in the CMS2 Tumour Subtype: A New Paradigm in CRC Treatment? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:75-100. [PMID: 30623367 DOI: 10.1007/978-3-030-02771-1_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancers (CRC) belonging to the consensus molecular subtype 2 (CMS2) have the highest incidence rate, affect mainly the distal colon and rectum, and are characterized by marked Wnt/β-catenin/Transcription Factor 7-Like 2 (TCF7L2) pathway activation and also by activation of epidermal growth factor receptor (EGFR) signalling. Despite having the highest overall survival, CMS2 tumours are often diagnosed at stage III when an adjuvant chemotherapy-based regimen is recommended. Nevertheless, colorectal cancer stem cells (CSCs) and circulating tumour cells may still evade the current therapeutic options and metastasize, stressing the need to develop more tailored therapeutic strategies. For example, activation of EGFR signalling is being used as a target for tailored therapy, however, therapy resistance is frequently observed. Therefore, targeting the Wnt signalling axis represents an additional therapeutic strategy, considering that CMS2 tumours are "Wnt-addicted". Several efforts have been made to identify Wnt antagonists, either of synthetic or natural origin. However, an inverse gradient of Wnt/β-catenin/TCF7L2 signalling activity during CRC progression has been suggested, with early stage and metastatic tumours displaying high and low Wnt signalling activities, respectively, which lead us to revisit the "just-right" signalling model. This may pinpoint the use of Wnt signalling agonists instead of antagonists for treatment of metastatic stages, in a context-dependent fashion. Moreover, the poor immunogenicity of these tumours challenges the use of recently emerged immunotherapies. This chapter makes a journey about CMS2 tumour characterization, their conventional treatment, and how modulation of Wnt signalling or immune response may be applied to CRC therapy. It describes the newest findings in this field and indicates where more research is required.
Collapse
Affiliation(s)
- Cristina Albuquerque
- Molecular Pathobiology Research Unit, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E., Lisbon, Portugal.
| | - Lucília Pebre Pereira
- Molecular Pathobiology Research Unit, Portuguese Institute of Oncology of Lisbon Francisco Gentil, E.P.E., Lisbon, Portugal
| |
Collapse
|
|
44
|
Activation of Peroxisome Proliferator-activated Receptor γ Prevents Development of Heart Failure With Preserved Ejection Fraction; Inhibition of Wnt-β-catenin Signaling as a Possible Mechanism. J Cardiovasc Pharmacol 2017; 68:155-61. [PMID: 27046338 DOI: 10.1097/fjc.0000000000000397] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Left ventricular (LV) fibrosis plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). We investigated whether chronic peroxisome proliferator-activated receptor gamma agonism with pioglitazone can prevent the development of HFpEF. We also evaluated the role of Wnt-β-catenin signaling in the development of HFpEF, and its relationship to peroxisome proliferator-activated receptor gamma signaling. Dahl salt-sensitive rats placed on an 8% NaCl diet from age 6 weeks were used as HFpEF model. Rats placed on 0.3% NaCl diet served as controls (n = 7). HFpEF model rats were randomized to no treatment (n = 7) or treatment with pioglitazone (2.5 mg/kg per day, n = 7) at age 13 weeks. Pioglitazone administration from age 13 to 21 weeks attenuated the development of LV fibrosis and stiffening (both P < 0.05), and subsequently prevented the development of HFpEF. In the untreated HFpEF model, Wnt1, 2, 10b messenger RNA and β-catenin protein expression levels in the left ventricle increased in the heart failure stage, along with the increase in type I collagen messenger RNA expression levels. Administration of pioglitazone attenuated the activation of Wnt-β-catenin signaling. Our results show that pioglitazone prevented the development of LV fibrosis and HFpEF in a rat model, at least partly due to attenuated Wnt-β-catenin signaling.
Collapse
|
|
45
|
Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer's disease. Acta Biochim Biophys Sin (Shanghai) 2017; 49:853-866. [PMID: 28981597 DOI: 10.1093/abbs/gmx073] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 06/23/2017] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aβ) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/β-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/β-catenin, through activation of glycogen synthase kinase-3β (GSK-3β) by Aβ, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aβ-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3β, an inhibitor of Wnt pathway. CBD may also increase Wnt/β-catenin by stimulation of PPARγ, inhibition of Aβ and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.
Collapse
Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France
| | | | - Rémy Guillevin
- Université de Poitiers et CHU de Poitiers, DACTIM, Laboratoire de Mathématiques et Applications, UMR CNRS 7348, SP2MI, Futuroscope, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France
- CHU Amiens Picardie, Université Picardie Jules Verne (UPJV), Amiens, France
| |
Collapse
|
|
46
|
Gao M, Chen T, Wu L, Zhao X, Mao H, Xing C. Effect of pioglitazone on the calcification of rat vascular smooth muscle cells through the downregulation of the Wnt/β‑catenin signaling pathway. Mol Med Rep 2017; 16:6208-6213. [PMID: 28849074 DOI: 10.3892/mmr.2017.7308] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 07/03/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effect and possible mechanism of pioglitazone (PIO) on the calcification of rat vascular smooth muscle cells (VSMCs) in vitro. β‑glycerophosphate (β‑GP; 10 mmol/l) was used to induce calcification of VSMCs treated with a range of concentrations (5, 10, 15 and 20 µmol/l) of PIO for 12 days. Calcium deposits were revealed by Alizarin red staining. Extracellular calcium content was detected using a calcium assay kit. Western blotting was used to measure the expression of α‑smooth muscle actin (α‑SMA), runt‑related transcription factor 2 (Runx2), bone morphogenetic protein‑2 (BMP2), β‑catenin, glycogen synthase kinase‑3β (GSK‑3β), phosphorylated (p)‑GSK‑3β and cyclin‑D1. A total of 10 mmol/l β‑GP, 20 µmol/l PIO and 20 µmol/l peroxisome proliferator‑activated receptor γ (PPAR γ) antagonist GW9662, was added to the cell culture media. The changes of the above indexes were observed. The calcium content in the calcification group, treated with high phosphorus, increased significantly compared with the controls (P<0.05) and all different concentrations of PIO reduced extracellular calcium content (P<0.05). Alizarin red staining was positive in calcified VSMCs and PIO (20 µmol/l) intervention group was almost negative. The expressions of Runx2, β‑catenin, p‑GSK‑3β, BMP2 and cyclin‑D1 increased significantly in the calcification group, and treatment with 20 µmol/l PIO downregulated the expression of all the above proteins, while upregulating the expression of α‑SMA. The PPAR γ antagonist GW9662 could partly inhibit the effect of PIO on calcified VSMCs. The results of the present study indicated that PIO can alleviate the calcification of rat aortic VSMCs induced by β‑GP via inhibiting the activity of the Wnt/β‑catenin signaling pathway.
Collapse
Affiliation(s)
- Min Gao
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Tianlei Chen
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Lin Wu
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiufen Zhao
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Huijuan Mao
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Changying Xing
- Department of Nephrology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| |
Collapse
|
|
47
|
Bao H, Zhang Q, Zhu Z, Xu H, Ding F, Wang M, Du S, Du Y, Yan Z. BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/β-catenin signalling. Sci Rep 2017; 7:9153. [PMID: 28831201 PMCID: PMC5567253 DOI: 10.1038/s41598-017-09655-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/26/2017] [Indexed: 12/17/2022] Open
Abstract
The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/β-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose-dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down-regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased β-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer.
Collapse
Affiliation(s)
- Hanmei Bao
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Qing Zhang
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Zhongling Zhu
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Hui Xu
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Fengxia Ding
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Meisa Wang
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Shuangshuang Du
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Yibo Du
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Zhao Yan
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
| |
Collapse
|
|
48
|
Emons G, Spitzner M, Reineke S, Möller J, Auslander N, Kramer F, Hu Y, Beissbarth T, Wolff HA, Rave-Fränk M, Heßmann E, Gaedcke J, Ghadimi BM, Johnsen SA, Ried T, Grade M. Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling. Mol Cancer Res 2017; 15:1481-1490. [PMID: 28811361 DOI: 10.1158/1541-7786.mcr-17-0205] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/11/2017] [Accepted: 08/08/2017] [Indexed: 01/21/2023]
Abstract
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. ©2017 AACR.
Collapse
Affiliation(s)
- Georg Emons
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany.,Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Melanie Spitzner
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Sebastian Reineke
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Janneke Möller
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Noam Auslander
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Frank Kramer
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Yue Hu
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Tim Beissbarth
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Hendrik A Wolff
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, Goettingen, Germany.,Department of Radiology, Nuclear Medicine and Radiotherapy, Radiology Munich, Munich, Germany
| | - Margret Rave-Fränk
- Department of Radiotherapy and Radiooncology, University Medical Center Goettingen, Goettingen, Germany
| | - Elisabeth Heßmann
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Jochen Gaedcke
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - B Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Steven A Johnsen
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany
| | - Thomas Ried
- Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland
| | - Marian Grade
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany.
| |
Collapse
|
|
49
|
Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway. Cell Death Dis 2017; 8:e2799. [PMID: 28518143 PMCID: PMC5520714 DOI: 10.1038/cddis.2017.193] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 03/27/2017] [Accepted: 03/29/2017] [Indexed: 12/17/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a major complication and fatal cause of the patients with diabetes. The calcium sensing receptor (CaSR) is a G protein-coupled receptor, which is involved in maintaining calcium homeostasis, regulating cell proliferation and apoptosis, and so on. In our previous study, we found that CaSR expression, intracellular calcium levels and cardiac function were all significantly decreased in DCM rats; however, the exact mechanism are not clear yet. The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose (HG) as well as the underlying mechanism. Here, we demonstrated that HG decreased the expression of CaSR, mitochondrial fusion proteins (Mfn1, Mfn2), cell gap junction related proteins (Cx43, β-catenin, N-cadherin), and intracellular ATP concentration. In contrast, HG increased extracellular ATP concentration, the expression of gp78, mitochondrial fission proteins (Fis1, Drp1), and the ubiquitination levels of Mfn1, Mfn2 and Cx43. Moreover, CaSR agonist and gp78-siRNA significantly reduced the above changes. Taken together, these results suggest that HG induces myocardial energy metabolism disorder via decrease of CaSR expression, and activation of gp78-ubiquitin proteasome system. In turn, these effects disrupt the structure and function of the mitochondria and the cell gap junction, result in the reduced ATP synthesis and the increased ATP leakage. Stimulation of CaSR significantly attenuates HG-induced abnormal myocardial energy metabolism, suggesting CaSR would be a promising potential therapeutic target for DCM.
Collapse
|
|
50
|
LiCl Treatment Induces Programmed Cell Death of Schwannoma Cells through AKT- and MTOR-Mediated Necroptosis. Neurochem Res 2017; 42:2363-2371. [DOI: 10.1007/s11064-017-2256-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 03/29/2017] [Accepted: 03/30/2017] [Indexed: 12/21/2022]
|