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Rižner TL, Gjorgoska M. Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives. Essays Biochem 2024; 68:411-422. [PMID: 38994718 PMCID: PMC11625860 DOI: 10.1042/ebc20230096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/07/2024] [Accepted: 06/26/2024] [Indexed: 07/13/2024]
Abstract
Sulfatase (STS) and sulfotransferases (SULT) have important role in the biosynthesis and action of steroid hormones. STS catalyzes the hydrolysis of estrone-sulfate (E1-S) and dehydroepiandrosterone-sulfate (DHEA-S), while sulfotransferases catalyze the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate as a sulfate donor. These enzymes control the concentration of active estrogens and androgens in peripheral tissues. Aberant expression of STS and SULT genes has been found in both, benign hormone-dependent diseases and hormone-dependent cancers. The aim of this review is to present the current knowledge on the role of STS and SULT in gynecological cancers, endometrial (EC) and ovarian cancer (OC). EC is the most common and OC the most lethal gynecological cancer. These cancers primarily affect postmenopausal women and therefore rely on the local production of steroid hormones from inactive precursors, either DHEA-S or E1-S. Following cellular uptake by organic anion transporting polypeptides (OATP) or organic anion transporters (OAT), STS and SULT regulate the formation of active estrogens and androgens, thus disturbed balance between STS and SULT can contribute to the onset and progression of cancer. The importance of these enzymes in peripheral estrogen biosynthesis has long been recognized, and this review provides new data on the important role of STS and SULT in the formation and action of androgens, their regulation and inhibition, and their potential as prognostic biomarkers.
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Affiliation(s)
- Tea Lanišnik Rižner
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Marija Gjorgoska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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2
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Kwon TU, Kwon YJ, Baek HS, Park H, Lee H, Chun YJ. Unraveling the molecular mechanisms of cell migration impairment and apoptosis associated with steroid sulfatase deficiency: Implications for X-linked ichthyosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167004. [PMID: 38182070 DOI: 10.1016/j.bbadis.2023.167004] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 01/07/2024]
Abstract
Steroid sulfatase (STS) deficiency is responsible for X-linked ichthyosis (XLI), a genetic disorder characterized by rough and dry skin caused by excessive keratinization. The impaired keratinization process leads to reduced cell mobility and increased apoptosis, which can cause an excessive buildup of the stratum corneum. In this study, we investigated the mechanisms underlying XLI and found that STS deficiency reduces cell mobility and increases apoptosis in human keratinocyte HaCaT cells. To explore these mechanisms further, RNA-sequencing was conducted on skin tissues from STS transgenic and knockout mice. Our RNA-seq results revealed that STS deficiency plays a critical role in regulating multiple signaling pathways associated with cell mobility and apoptosis, such as Wnt/β signaling and the Hippo signaling pathway. Knockdown of the STS gene using shRNA in HaCaT cells led to an upregulation of E-cadherin expression and suppression of key factors involved in epithelial-mesenchymal transition (EMT), such as N-cadherin and vimentin. Inhibition of EMT involved the Hippo signaling pathway and reduction of HIF-1α. Interestingly, inhibiting STS with shRNA increased mitochondrial respiration levels, as demonstrated by the extracellular flux oxygen consumption rate. Additionally, we observed a significant increase in ROS production in partial STS knockout cells compared to control cells. Our study demonstrated that the excessive generation of ROS caused by STS deficiency induces the expression of Bax and Bak, leading to the release of cytochrome c and subsequent cell death. Consequently, STS deficiency impairs cell mobility and promotes apoptosis, offering insights into the pathophysiological processes and potential therapeutic targets for XLI.
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Affiliation(s)
- Tae-Uk Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yeo-Jung Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyoung-Seok Baek
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyemin Park
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyein Lee
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea.
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3
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Alsaab HO. Pathological role of long non-coding (lnc) RNA in the regulation of Wnt/β-catenin signaling pathway during epithelial-mesenchymal transition (EMT). Pathol Res Pract 2023; 248:154566. [PMID: 37285735 DOI: 10.1016/j.prp.2023.154566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/09/2023]
Abstract
The term "epithelial-mesenchymal transition" (EMT) describes a biological process wherein epithelial cells acquire mesenchymal cell characteristics. This process enables the metastatic cells to migrate and invasion. Recent studies have established the connections between the EMT process and Wnt/β-catenin signaling in cancer. Key cellular functions such as differentiation, proliferation, migration, genetic stability, apoptosis, and stem cell renewal are modulated via Wnt/ β-catenin signaling pathway. Up-regulation of this evolutionarily conserved signal pathway leads to EMT. On the other hand, recent investigations have indicated that non-coding RNAs including microRNAs (miRNAs) and long non-coding RNA (lncRNAs) are involved in regulating of Wnt/β-catenin pathway. A high level of lncRNAs mainly has a positive correlation with EMT. However, lncRNA down-regulation has been observed in promoting EMT. It seems that depending on the specific targets, up-or down-regulation of lncRNAs can stimulate EMT by activating the Wnt/ β-catenin pathway. The evaluation of interactions between lncRNAs and the Wnt/ β-catenin signaling pathway in the regulation of EMT during metastasis can be fascinating. Herein, for the first time, the crucial role of lncRNAs-mediated regulation of the Wnt/ β-catenin signaling pathway in the EMT process of human tumors has been summarized.
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Affiliation(s)
- Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia.
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Herrera JA, Dingle L, Montero MA, Venkateswaran RV, Blaikley JF, Lawless C, Schwartz MA. The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix. JCI Insight 2022; 7:e156115. [PMID: 35852874 PMCID: PMC9462507 DOI: 10.1172/jci.insight.156115] [Citation(s) in RCA: 21] [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: 11/19/2021] [Accepted: 07/07/2022] [Indexed: 11/17/2022] Open
Abstract
Usual interstitial pneumonia (UIP) is a histological pattern characteristic of idiopathic pulmonary fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection-coupled mass spectrometry, we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subjected to qualitative and quantitative analysis and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.
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Affiliation(s)
| | - Lewis Dingle
- Blond McIndoe Laboratories, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - M. Angeles Montero
- Department of Histopathology, Manchester University National Health Service Foundation Trust, Manchester, United Kingdom
| | - Rajamiyer V. Venkateswaran
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Department of Transplant, Manchester University National Health Service Foundation Trust, Manchester, United Kingdom
| | - John F. Blaikley
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Department of Transplant, Manchester University National Health Service Foundation Trust, Manchester, United Kingdom
| | | | - Martin A. Schwartz
- The Wellcome Centre for Cell-Matrix Research and
- Yale Cardiovascular Research Center and
- Departments of Internal Medicine (Cardiology) and Cell Biology, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, Connecticut, USA
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5
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Luo Y, Vlaeminck-Guillem V, Baron S, Dallel S, Zhang CX, Le Romancer M. MEN1 silencing aggravates tumorigenic potential of AR-independent prostate cancer cells through nuclear translocation and activation of JunD and β-catenin. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:270. [PMID: 34446068 PMCID: PMC8393735 DOI: 10.1186/s13046-021-02058-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/02/2021] [Indexed: 11/16/2022]
Abstract
Background Recent studies highlighted the increased frequency of AR-low or -negative prostate cancers (PCas) and the importance of AR-independent mechanisms in driving metastatic castration-resistant PCa (mCRPC) development and progression. Several previous studies have highlighted the involvement of the MEN1 gene in PCa. In the current study, we focused on its role specifically in AR-independent PCa cells. Methods Cell tumorigenic features were evaluated by proliferation assay, foci formation, colony formation in soft agar, wound healing assay and xenograft experiments in mice. Quantitative RT-PCR, Western blot and immunostaining were performed to determine the expression of different factors in human PCa lines. Different ChIP-qPCR-based assays were carried out to dissect the action of JunD and β-catenin. Results We found that MEN1 silencing in AR-independent cell lines, DU145 and PC3, resulted in an increase in anchorage independence and cell migration, accompanied by sustained MYC expression. By searching for factors known to positively regulate MYC expression and play a relevant role in PCa development and progression, we uncovered that MEN1-KD triggered the nuclear translocation of JunD and β-catenin. ChIP and 3C analyses further demonstrated that MEN1-KD led to, on the one hand, augmented binding of JunD to the MYC 5′ enhancer and increased formation of loop structure, and on the other hand, increased binding of β-catenin to the MYC promoter. Moreover, the expression of several molecular markers of EMT, including E-cadherin, BMI1, Twist1 and HIF-1α, was altered in MEN1-KD DU145 and PC3 cells. In addition, analyses using cultured cells and PC3-GFP xenografts in mice demonstrated that JunD and β-catenin are necessary for the altered tumorigenic potential triggered by MEN1 inactivation in AR-independent PCa cells. Finally, we observed a significant negative clinical correlation between MEN1 and CTNNB1 mRNA expression in primary PCa and mCRPC datasets. Conclusions Our current work highlights an unrecognized oncosuppressive role for menin specifically in AR-independent PCa cells, through the activation of JunD and β-catenin pathways. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02058-7.
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Affiliation(s)
- Yakun Luo
- Université Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 69008, Lyon, France
| | - Virginie Vlaeminck-Guillem
- Université Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 69008, Lyon, France.,Centre de biologie Sud, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310, Pierre-Bénite, France
| | - Silvère Baron
- Université Clermont Auvergne, GReD, CNRS UMR 6293, INSERM U1103, 28 Place Henri Dunant, BP38, 63001, Clermont-Ferrand, France
| | - Sarah Dallel
- Université Clermont Auvergne, GReD, CNRS UMR 6293, INSERM U1103, 28 Place Henri Dunant, BP38, 63001, Clermont-Ferrand, France
| | - Chang Xian Zhang
- Université Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 69008, Lyon, France.
| | - Muriel Le Romancer
- Université Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 69008, Lyon, France
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Zhao Z, Wu X, Cheng Y, Zhou Y, Ma X, Zhang J, Heng X, Feng F. TROAP regulates cell cycle and promotes tumor progression through Wnt/β-Catenin signaling pathway in glioma cells. CNS Neurosci Ther 2021; 27:1064-1076. [PMID: 34077623 PMCID: PMC8339535 DOI: 10.1111/cns.13688] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/02/2021] [Accepted: 05/17/2021] [Indexed: 12/28/2022] Open
Abstract
AIMS Experimental evidence demonstrated a crucial role of TROAP (Trophinin-associated protein) in regulating the cell proliferation of multiple tumors, while TROAP expression and function were largely unknown in glioma. We aimed to investigate the oncogenic role of TROAP and its potential mechanisms in gliomagenesis. METHODS Four gene expression databases (GEO, TCGA, GTEx and CCLE) were enrolled in our study and used for TROAP expression and survival analysis. TROAP expression was quantified by qRT-PCR, western blot and immunohistochemistry assays in glioma tissues and cell lines. TROAP knockdown and overexpression vector were constructed and transfected into glioma cells. CCK-8, colony formation, transwell, and wound healing assays were used to evaluate cell viability, migration and invasion, flow cytometry to determine cell cycle arrest. Gene set enrichment analysis (GSEA) was conducted to screen the pathway involved in TROAP-high phenotype. The expression of cell cycle and Wnt/β-Catenin signaling proteins were analyzed by immunofluorescence and western blot. RESULTS Based on the bioinformatic analysis and a series of functional assays, we found the TROAP was enriched in glioma tissues and cell lines, its overexpression was correlated with the clinicopathologic characteristics and poor prognosis. TROAP knockdown inhibited cell proliferation, migration, invasion, and G1/S cell cycle arrest compared with control group in glioma. Mechanism analysis revealed that TROAP activated Wnt/β-Catenin pathway and upregulated its downstream targets expression, while silencing β-Catenin or Axin2 could reverse the tumor-promoting effects caused by TROAP, confirming that TROAP-induced malignant phenotype and tumorigenesis via Wnt/β-Catenin signaling pathway. CONCLUSION The present study found that TROAP accelerated the progression of gliomagenesis through Wnt/β-Catenin pathway, and TROAP might be considered as a novel target for glioma therapy.
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Affiliation(s)
- Zong‐qing Zhao
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Xiu‐jie Wu
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Yan‐hao Cheng
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Yun‐fei Zhou
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Xi‐meng Ma
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Jian Zhang
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Xue‐yuan Heng
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
| | - Fan Feng
- Department of NeurosurgeryLinyi People’s HospitalLinyiChina
- Institute of Brain Science and Brain‐Like IntelligenceLinyi People’s HospitalLinyiChina
- Institute of Clinical Medicine CollegeGuangzhou University of Chinese MedicineGuangzhouChina
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7
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Zada S, Hwang JS, Ahmed M, Lai TH, Pham TM, Elashkar O, Kim DR. Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188565. [PMID: 33992723 DOI: 10.1016/j.bbcan.2021.188565] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/05/2021] [Accepted: 05/08/2021] [Indexed: 02/07/2023]
Abstract
Autophagy is a highly conserved metabolic process involved in the degradation of intracellular components including proteins and organelles. Consequently, it plays a critical role in recycling metabolic energy for the maintenance of cellular homeostasis in response to various stressors. In cancer, autophagy either suppresses or promotes cancer progression depending on the stage and cancer type. Epithelial-mesenchymal transition (EMT) and cancer metastasis are directly mediated by oncogenic signal proteins including SNAI1, SLUG, ZEB1/2, and NOTCH1, which are functionally correlated with autophagy. In this report, we discuss the crosstalk between oncogenic signaling pathways and autophagy followed by possible strategies for cancer treatment via regulation of autophagy. Although autophagy affects EMT and cancer metastasis, the overall signaling pathways connecting cancer progression and autophagy are still illusive. In general, autophagy plays a critical role in cancer cell survival by providing a minimum level of energy via self-digestion. Thus, cancer cells face nutrient limitations and challenges under stress during EMT and metastasis. Conversely, autophagy acts as a potential cancer suppressor by degrading oncogenic proteins, which are essential for cancer progression, and by removing damaged components such as mitochondria to enhance genomic stability. Therefore, autophagy activators or inhibitors represent possible cancer therapeutics. We further discuss the regulation of autophagy-dependent degradation of oncogenic proteins and its functional correlation with oncogenic signaling pathways, with potential applications in cancer therapy.
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Affiliation(s)
- Sahib Zada
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Jin Seok Hwang
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Mahmoud Ahmed
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Trang Huyen Lai
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Trang Minh Pham
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Omar Elashkar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 527-27, Republic of Korea.
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8
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Foster PA. Steroid Sulphatase and Its Inhibitors: Past, Present, and Future. Molecules 2021; 26:2852. [PMID: 34064842 PMCID: PMC8151039 DOI: 10.3390/molecules26102852] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/22/2022] Open
Abstract
Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter's imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase-STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.
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Affiliation(s)
- Paul A. Foster
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK; ; Tel.: +44-121-414-3776
- Centre for Endocrinology, Metabolism and Diabetes, University of Birmingham, Birmingham Health Partners, Birmingham B15 2TT, UK
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9
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Anbar HS, Isa Z, Elounais JJ, Jameel MA, Zib JH, Samer AM, Jawad AF, El-Gamal MI. Steroid sulfatase inhibitors: the current landscape. Expert Opin Ther Pat 2021; 31:453-472. [PMID: 33783295 DOI: 10.1080/13543776.2021.1910237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Steroid sulfatase (STS) enzyme is responsible for transforming the inactive sulfate metabolites of steroid sex hormones into the active free steroids. Both the deficiency and the over-expression of STS are associated with the pathophysiology of certain diseases. This article provides the readership with a comprehensive review about STS enzyme and its recently reported inhibitors.Areas covered: In the present article, we reviewed the structure, location, and substrates of STS enzyme, physiological functions of STS, and disease states related to over-expression or deficiency of STS enzyme. STS inhibitors reported during the last five years (2016-present) have been reviewed as well.Expert opinion: Irosustat is the most successful STS inhibitor drug candidate so far. It is currently under investigation in clinical trials for treatment of estrogen-dependent breast cancer. Non-steroidal sulfamate is the most favorable scaffold for STS inhibitor design. They can be beneficial for the treatment of hormone-dependent cancers and neurodegenerative disorders without significant estrogenic side effects. Moreover, dual-acting molecules (inhibitors of STS + another synergistic mechanism) can be therapeutically efficient.
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Affiliation(s)
- Hanan S Anbar
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Zahraa Isa
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Jana J Elounais
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Mariam A Jameel
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Joudi H Zib
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Aya M Samer
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Aya F Jawad
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates
| | - Mohammed I El-Gamal
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.,Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
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10
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Du X, Song H, Shen N, Hua R, Yang G. The Molecular Basis of Ubiquitin-Conjugating Enzymes (E2s) as a Potential Target for Cancer Therapy. Int J Mol Sci 2021; 22:ijms22073440. [PMID: 33810518 PMCID: PMC8037234 DOI: 10.3390/ijms22073440] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 01/06/2023] Open
Abstract
Ubiquitin-conjugating enzymes (E2s) are one of the three enzymes required by the ubiquitin-proteasome pathway to connect activated ubiquitin to target proteins via ubiquitin ligases. E2s determine the connection type of the ubiquitin chains, and different types of ubiquitin chains regulate the stability and activity of substrate proteins. Thus, E2s participate in the regulation of a variety of biological processes. In recent years, the importance of E2s in human health and diseases has been particularly emphasized. Studies have shown that E2s are dysregulated in variety of cancers, thus it might be a potential therapeutic target. However, the molecular basis of E2s as a therapeutic target has not been described systematically. We reviewed this issue from the perspective of the special position and role of E2s in the ubiquitin-proteasome pathway, the structure of E2s and biological processes they are involved in. In addition, the inhibitors and microRNAs targeting E2s are also summarized. This article not only provides a direction for the development of effective drugs but also lays a foundation for further study on this enzyme in the future.
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11
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Coelho BP, Fernandes CFDL, Boccacino JM, Souza MCDS, Melo-Escobar MI, Alves RN, Prado MB, Iglesia RP, Cangiano G, Mazzaro GLR, Lopes MH. Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma. Front Oncol 2020; 10:597743. [PMID: 33312955 PMCID: PMC7706883 DOI: 10.3389/fonc.2020.597743] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/19/2020] [Indexed: 12/17/2022] Open
Abstract
Tumor cells can employ epithelial-mesenchymal transition (EMT) or autophagy in reaction to microenvironmental stress. Importantly, EMT and autophagy negatively regulate each other, are able to interconvert, and both have been shown to contribute to drug-resistance in glioblastoma (GBM). EMT has been considered one of the mechanisms that confer invasive properties to GBM cells. Autophagy, on the other hand, may show dual roles as either a GBM-promoter or GBM-suppressor, depending on microenvironmental cues. The Wingless (WNT) signaling pathway regulates a plethora of developmental and biological processes such as cellular proliferation, adhesion and motility. As such, GBM demonstrates deregulation of WNT signaling in favor of tumor initiation, proliferation and invasion. In EMT, WNT signaling promotes induction and stabilization of different EMT activators. WNT activity also represses autophagy, while nutrient deprivation induces β-catenin degradation via autophagic machinery. Due to the importance of the WNT pathway to GBM, and the role of WNT signaling in EMT and autophagy, in this review we highlight the effects of the WNT signaling in the regulation of both processes in GBM, and discuss how the crosstalk between EMT and autophagy may ultimately affect tumor biology.
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Affiliation(s)
- Bárbara Paranhos Coelho
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Camila Felix de Lima Fernandes
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Jacqueline Marcia Boccacino
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Maria Clara da Silva Souza
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Maria Isabel Melo-Escobar
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Nunes Alves
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Mariana Brandão Prado
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Rebeca Piatniczka Iglesia
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Giovanni Cangiano
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Giulia La Rocca Mazzaro
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
| | - Marilene Hohmuth Lopes
- Laboratory of Neurobiology and Stem Cells, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil
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12
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Armstrong CM, Liu C, Liu L, Yang JC, Lou W, Zhao R, Ning S, Lombard AP, Zhao J, D'Abronzo LS, Evans CP, Li PK, Gao AC. Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer. Clin Cancer Res 2020; 26:6064-6074. [PMID: 32928794 DOI: 10.1158/1078-0432.ccr-20-1682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 09/09/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer. EXPERIMENTAL DESIGN STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo. RESULTS STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo. CONCLUSIONS These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy.
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Affiliation(s)
- Cameron M Armstrong
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Chengfei Liu
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Liangren Liu
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Joy C Yang
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Wei Lou
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Ruining Zhao
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Shu Ning
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Alan P Lombard
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Jinge Zhao
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Leandro S D'Abronzo
- Department of Urologic Surgery, University of California, Davis, Sacramento, California
| | - Christopher P Evans
- Department of Urologic Surgery, University of California, Davis, Sacramento, California.,UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, California
| | - Pui-Kai Li
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Allen C Gao
- Department of Urologic Surgery, University of California, Davis, Sacramento, California. .,UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, California.,VA Northern California Health Care System, Sacramento, California
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13
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Wei H, Zhang F, Wang J, Zhao M, Hou T, Li L. Dehydroeffusol inhibits hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer cells through the inactivation of Wnt/β-catenin pathway. Biosci Rep 2020; 40:BSR20194284. [PMID: 32426814 PMCID: PMC7256677 DOI: 10.1042/bsr20194284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 05/06/2020] [Accepted: 05/18/2020] [Indexed: 01/02/2023] Open
Abstract
Dehydroeffusol (DHE) is a phenanthrene compound that possesses anti-tumor activity. However, the effect of DHE on non-small cell lung cancer (NSCLC) has not been investigated previously. Therefore, the objective of our study was to explore the role of DHE in NSCLC and the underlying mechanism. Our results showed that DHE significantly inhibited the cell viability of A549 cells in a dose- and time-dependent manner under normoxic condition. Moreover, A549 cells were more sensitive to DHE under hypoxic condition compared with the A549 cells cultured in normoxic condition. Hypoxia-induced increased migration and invasion abilities were mitigated by DHE in A549 cells. Treatment of DHE caused increased E-cadherin expression and decreased N-cadherin expression in hypoxia-induced A549 cells. DHE also suppressed hypoxia-induced increase in both protein and mRNA levels of hypoxia inducible factor-1α (HIF-1α) expression in A549 cells. Furthermore, DHE inhibited hypoxia-induced activation of Wnt/β-catenin pathway in A549 cells. The inhibitory effect of DHE on hypoxia-induced EMT was reversed by LiCl, which is an activator of Wnt/β-catenin signaling pathway. In conclusion, these findings demonstrated that DHE prevented hypoxia-induced EMT in NSCLC cells by inhibiting the activation of Wnt/β-catenin pathway, suggesting that DHE might serve as a therapeutic target for the NSCLC metastasis.
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MESH Headings
- A549 Cells
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antineoplastic Agents, Phytogenic/pharmacology
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Movement/drug effects
- Epithelial-Mesenchymal Transition/drug effects
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Neoplasm Invasiveness
- Phenanthrenes/pharmacology
- Tumor Hypoxia
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Haitao Wei
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Feng Zhang
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Jiali Wang
- Operating Room, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Min Zhao
- Department of Respiratory, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Tao Hou
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, P.R. China
| | - Li Li
- College of Nursing and Health, Henan University, Kaifeng 475001, P.R. China
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14
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Park S, Song CS, Lin CL, Jiang S, Osmulski PA, Wang CM, Marck BT, Matsumoto AM, Morrissey C, Gaczynska ME, Chen Y, Mostaghel EA, Chatterjee B. Inhibitory Interplay of SULT2B1b Sulfotransferase with AKR1C3 Aldo-keto Reductase in Prostate Cancer. Endocrinology 2020; 161:bqz042. [PMID: 31894239 PMCID: PMC7341717 DOI: 10.1210/endocr/bqz042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/30/2019] [Indexed: 12/22/2022]
Abstract
SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor for 5α-dihydrotestosterone (DHT) biosynthesis. The aldo-keto reductase (AKR)1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout (KO), are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal (EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B KO cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from 50 autopsy cases. Primary tumors showed variable and Gleason score (GS)-independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction, and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer.
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Affiliation(s)
- Sulgi Park
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
- Department of Microbiology & Immunology, Pusan National University School of Medicine, South Korea
- South Texas Veterans Health Care System, San Antonio, Texas
| | - Chung-Seog Song
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
- South Texas Veterans Health Care System, San Antonio, Texas
| | - Chun-Lin Lin
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Shoulei Jiang
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
- South Texas Veterans Health Care System, San Antonio, Texas
| | - Pawel A Osmulski
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Chiou-Miin Wang
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Brett T Marck
- Geriatric Research, Education & Clinical Center, VA Puget Sound Health Care System, Seattle, WA
| | - Alvin M Matsumoto
- Geriatric Research, Education & Clinical Center, VA Puget Sound Health Care System, Seattle, WA
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, WA
| | - Maria E Gaczynska
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Yidong Chen
- Department of Epidemiology & Biostatistics, University of Texas Health San Antonio, San Antonio, Texas
- Greehy Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas
| | - Elahe A Mostaghel
- Geriatric Research, Education & Clinical Center, VA Puget Sound Health Care System, Seattle, WA
- Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Bandana Chatterjee
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas
- South Texas Veterans Health Care System, San Antonio, Texas
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15
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Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X, Gong Z. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol Cancer 2020; 19:9. [PMID: 31941509 PMCID: PMC6961326 DOI: 10.1186/s12943-020-1133-9] [Citation(s) in RCA: 232] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 01/09/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) and Twist1-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination are well established, but the involvement of long noncoding RNAs (lncRNAs) in Twist1-mediated signaling remains largely unknown. METHODS RT-qPCR and western blotting were conducted to detect the expression levels of lncRNA JPX and Twist1 in lung cancer cell lines and tissues. The impact of JPX on Twist1 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by western blotting, rescue experiments, colony formation assay, flow cytometry, and xenograft animal experiment. RESULTS We observed that lncRNA JPX was upregulated in lung cancer metastatic tissues and was closely correlated with tumor size and an advanced stage. Functionally, JPX promoted lung cancer cell proliferation in vitro and facilitated lung tumor growth in vivo. Additionally, JPX upregulated Twist1 by competitively sponging miR-33a-5p and subsequently induced EMT and lung cancer cell invasion. Interestingly, JPX and Twist1 were coordinately upregulated in lung cancer tissues and cells. Mechanically, the JPX/miR-33a-5p/Twist1 axis participated in EMT progression by activating Wnt/β-catenin signaling. CONCLUSIONS These findings suggest that lncRNA JPX, a mediator of Twist1 signaling, could predispose lung cancer cells to metastasis and may serve as a potential target for targeted therapy.
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Affiliation(s)
- Jinchang Pan
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
| | - Shuai Fang
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
| | - Haihua Tian
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
- Department of Laboratory Medicine, The Affiliated Ningbo Kangning Hospital of Ningbo University School of Medicine, Ningbo, 315201, China
| | - Chengwei Zhou
- Department of Thoracic Surgery, The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, 315020, China
| | - Xiaodong Zhao
- Department of Thoracic Surgery, The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, 315020, China
| | - Hui Tian
- Department of Thoracic Surgery, The Affiliated Ningbo Medical Center Lihuili Eastern Hospital of Ningbo University School of Medicine, Ningbo, 315048, China
| | - Jinxian He
- Department of Thoracic Surgery, The Affiliated Ningbo Medical Center Lihuili Eastern Hospital of Ningbo University School of Medicine, Ningbo, 315048, China
| | - Weiyu Shen
- Department of Thoracic Surgery, The Affiliated Ningbo Medical Center Lihuili Eastern Hospital of Ningbo University School of Medicine, Ningbo, 315048, China
| | - Xiaodan Meng
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
| | - Zhaohui Gong
- Department of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, 315211, China.
- Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China.
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16
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Chen M, Tang B, Xie S, Yan J, Yang L, Zhou X, Zeng E. Biological Functions of TNKS1 and Its Relationship with Wnt/β-Catenin Pathway in Astrocytoma. Onco Targets Ther 2019; 12:10841-10850. [PMID: 31849489 PMCID: PMC6912014 DOI: 10.2147/ott.s206142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 11/05/2019] [Indexed: 11/23/2022] Open
Abstract
Background Tankyrase1 (TNKS1), which often shows abnormal expression in many malignant tumor cells, plays an important role in tumor progression. In our previous study, we found that TNKS1 is also closely related to pathologic grade in human astrocytoma and its expression level is positively correlated with the Wnt/β-catenin pathway. This study is aimed to further elucidate the biological functions of TNKS1 as well as its relationship with the Wnt/β-catenin pathway. Methods TNSK1 overexpression and knockdown vectors were constructed and transfected into glioblastoma cell lines U251 MG and U87, respectively. Viability, apoptosis, cell cycle and cell invasiveness in the treated cells were investigated. Results In comparison with untreated cells, U251 and U87 cells overexpressing TNSK1 showed significantly increased cell viability and decreased apoptosis, while the TNKS1 knockdown U251 and U87 cells had reduced cell invasive ability and increased apoptosis, respectively. In addition, immunoprecipitation study showed that TNKS1 could be detected by β-catenin antibody after pull-down, indicating that TNKS1 directly interacts with β-catenin, further indicating that TNKS1 could be regarded as a positive regulator of the Wnt/β-catenin pathway in astrocytoma. Moreover, knockdown of TNKS1 in U251 and U87 cells also leads to suppressed Wnt/β-catenin signaling, and subsequent decrease of cell growth and proliferation, reduced invasion ability and increased apoptosis. Conclusion Our findings suggest that TNKS1 might be a potential new therapeutic target for human astrocytoma in gene therapy.
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Affiliation(s)
- Min Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Bin Tang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
| | - Shenhao Xie
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
| | - Jian Yan
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
| | - Le Yang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
| | - Xinhui Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
| | - Erming Zeng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, Republic of China
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17
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Shin S, Kwon YJ, Ye DJ, Baek HS, Kwon TU, Kim D, Chun YJ. Human steroid sulfatase enhances aerobic glycolysis through induction of HIF1α and glycolytic enzymes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2464-2474. [PMID: 31195119 DOI: 10.1016/j.bbadis.2019.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/10/2019] [Accepted: 06/05/2019] [Indexed: 11/25/2022]
Abstract
Human steroid sulfatase (STS) has been linked with poor prognosis in steroid-associated tumors and represents an important clinical target in cancers, yet the mechanism of STS-induced carcinogenesis remains unclear. To correlate STS with cancer metabolism, we determined the effects of STS on aerobic glycolysis. STS overexpression increased cellular levels of lactic acid, the final product of aerobic glycolysis. Moreover, STS suppressed the oxygen consumption rate (OCR), which represents mitochondrial respiration. Inhibition of STS by the specific inhibitor STX064 recovered STS-induced OCR repression and lactic acid over-production. DHEA, but not DHEA-S, suppressed the OCR level and enhanced lactic acid production. To understand the molecular mechanism of STS-induced cancer metabolism, we measured the expression of glycolytic enzymes hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), which was highly upregulated by STS and DHEA at both protein and mRNA levels. HIF1α is a key mediator of aerobic glycolysis, and STS enhanced HIF1α promoter activity, mRNA expression, and protein expression. Down-regulation of HIF1α by siRNA suppressed the HK2 and PKM2 expression induced by both STS and DHEA. HIF1α siRNA also recovered the OCR repression and lactic acid over-production induced by both STS and DHEA. To explore the mechanism in vivo, we produced transgenic mice overexpressing STS and found that STS expression was particularly enhanced in the lung. Consistent with our in vitro results, the expression of HIF1α, HK2, and PKM2 was also increased in mouse lung tissues. In conclusion, we suggest that STS may induce aerobic glycolysis through enhancing HIF1α expression.
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Affiliation(s)
- Sangyun Shin
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
| | - Yeo-Jung Kwon
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
| | - Dong-Jin Ye
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
| | - Hyoung-Seok Baek
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
| | - Tae-Uk Kwon
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
| | - Donghak Kim
- Department of Biological Sciences, Konkuk University, Seoul, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
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18
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H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer. Int J Mol Sci 2019; 20:ijms20164012. [PMID: 31426484 PMCID: PMC6720303 DOI: 10.3390/ijms20164012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 08/14/2019] [Indexed: 12/24/2022] Open
Abstract
Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules’ expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells’ metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion.
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Chen HT, Liu H, Mao MJ, Tan Y, Mo XQ, Meng XJ, Cao MT, Zhong CY, Liu Y, Shan H, Jiang GM. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer 2019; 18:101. [PMID: 31126310 PMCID: PMC6533683 DOI: 10.1186/s12943-019-1030-2] [Citation(s) in RCA: 215] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 05/15/2019] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a highly conserved catabolic process that mediates degradation of pernicious or dysfunctional cellular components, such as invasive pathogens, senescent proteins, and organelles. It can promote or suppress tumor development, so it is a “double-edged sword” in tumors that depends on the cell and tissue types and the stages of tumor. The epithelial-mesenchymal transition (EMT) is a complex biological trans-differentiation process that allows epithelial cells to transiently obtain mesenchymal features, including motility and metastatic potential. EMT is considered as an important contributor to the invasion and metastasis of cancers. Thus, clarifying the crosstalk between autophagy and EMT will provide novel targets for cancer therapy. It was reported that EMT-related signal pathways have an impact on autophagy; conversely, autophagy activation can suppress or strengthen EMT by regulating various signaling pathways. On one hand, autophagy activation provides energy and basic nutrients for EMT during metastatic spreading, which assists cells to survive in stressful environmental and intracellular conditions. On the other hand, autophagy, acting as a cancer-suppressive function, is inclined to hinder metastasis by selectively down-regulating critical transcription factors of EMT in the early phases. Therefore, the inhibition of EMT by autophagy inhibitors or activators might be a novel strategy that provides thought and enlightenment for the treatment of cancer. In this article, we discuss in detail the role of autophagy and EMT in the development of cancers, the regulatory mechanisms between autophagy and EMT, the effects of autophagy inhibition or activation on EMT, and the potential applications in anticancer therapy.
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Affiliation(s)
- Hong-Tao Chen
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 2528000, Guangdong, China
| | - Hao Liu
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Min-Jie Mao
- Department of Laboratory Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yuan Tan
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 2528000, Guangdong, China.,Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xiang-Qiong Mo
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Xiao-Jun Meng
- Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Meng-Ting Cao
- Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Chu-Yu Zhong
- Department of Geriatrics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yan Liu
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 2528000, Guangdong, China
| | - Hong Shan
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 2528000, Guangdong, China.
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 2528000, Guangdong, China.
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Zha H, Li X, Sun H, Duan L, Yuan S, Li H, Li A, Gu Y, Zhao J, Xie J, Zhou L. S100A9 promotes the proliferation and migration of cervical cancer cells by inducing epithelial‑mesenchymal transition and activating the Wnt/β‑catenin pathway. Int J Oncol 2019; 55:35-44. [PMID: 31059008 PMCID: PMC6561615 DOI: 10.3892/ijo.2019.4793] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 04/03/2019] [Indexed: 01/02/2023] Open
Abstract
S100 calcium-binding protein A9 (S100A9), a member of the S100 protein family, is often upregulated in various cancers, including cervical cancer. Elevated S100A9 expression is thought to serve an important role in tumorigenesis; however, the exact role of S100A9 in the modulation of cervical cancer and the underlying molecular mechanism remain unknown. In the present study, we aimed to investigate the effects of S100A9 on the proliferation and migration of cervical cancer cells, as well as the molecular mechanisms underlying these effects. Our results demonstrated that endogenous expression of S100A9 in SiHa and CaSki cell lines was significantly higher than in the HeLa cell line. As expected, overexpression of S100A9 enhanced the proliferation and migration of cervical cancer cells. In addition, S100A9 overexpression induced epithelial-mesenchymal transition (EMT) as determined by reduced expression levels of the epithelial marker E-cadherin, whereas the expression levels of the mesenchymal marker vimentin were upregulated. Furthermore, it was reported that the effects of S100A9 in the modulation of cervical cancer cells were mediated through the Wnt/β-catenin signaling pathway as β-catenin knockdown significantly suppressed the ability of S100A9 to enhance the proliferation and migration of cervical cancer cells. Collectively, these findings suggest that S100A9 promoted the proliferation and migration of cervical cancer cell lines. Furthermore, the underlying molecular mechanisms may be partially attributed to the induction of EMT and activation of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- He Zha
- Department of Laboratory Medicine, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xueru Li
- Sichuan Academy of Medical Sciences and Institute of Dermatology and Venereal Disease, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610031, P.R. China
| | - Hui Sun
- Department of Laboratory Medicine, The First Hospital of Xi'an, Xi'an, Shaanxi 710002, P.R. China
| | - Liang Duan
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shimei Yuan
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Huan Li
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Aifang Li
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yue Gu
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jiali Zhao
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jiaqing Xie
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Lan Zhou
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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21
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Maurya N, Singh R, Goel A, Singhai A, Singh UP, Agrawal V, Garg M. Clinicohistopathological implications of phosphoserine 9 glycogen synthase kinase-3β/ β-catenin in urinary bladder cancer patients. World J Clin Oncol 2019; 10:166-182. [PMID: 31114749 PMCID: PMC6506422 DOI: 10.5306/wjco.v10.i4.166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 01/25/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Aberrant activation of phosphorylated form of glycogen synthase kinase-3β [pS9GSK-3β (Serine 9 phosphorylation)] is known to trigger Wnt/β-catenin signal cascade but its clinicohistopathological implications in bladder carcinogenesis remain unknown. AIM To investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3β, β-catenin and its target genes in the pathobiology of bladder cancer. METHODS Bladder tumor tissues from ninety patients were analyzed for quantitative expression and cellular localization of pS9GSK-3β by immunohistochemical (IHC) staining. Real time-quantitative polymerase chain reaction and IHC were done to check the expression of β-catenin, Cyclin D1, Snail and Slug at transcriptome and protein level respectively. Clinicohistopathological variables were obtained from histology reports, follow up and OPD visits of patients. Expressions of the markers were statistically correlated with these variables to determine their significance in clinical setting. Results were analysed using SPSS 20.0 software. RESULTS Aberrant (low or no membranous/high nuclear/high cytoplasmic) expression of pS9GSK-3β was noted in 51% patients and found to be significantly associated with tumor stage and tumor grade (P = 0.01 and 0.04; Mann Whitney U test). Thirty one percent tumors exhibited aberrant co-expression of pS9GSK-3β and β-catenin proteins and showed strong statistical association with tumor stage, tumor type, smoking/tobacco chewing status (P = 0.01, 0.02 and 0.04, Mann-Whitney U test) and shorter overall survival probabilities of patients (P = 0.02; Kaplan Meier test). Nuclear immunostaining of Cyclin D1 in tumors with altered pS9GSK-3β/β-catenin showed relevance with tumor stage, grade and type. CONCLUSION β-catenin and pS9GSK-3β proteins are identified as markers of diagnostic/prognostic significance in disease pathogenesis. Observed histopathological association of Cyclin D1 identifies it as marker of potential relevance in tumors with altered pS9GSK-3β/β-catenin.
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Affiliation(s)
- Niharika Maurya
- Department of Biochemistry, Lucknow University, Lucknow 226007, India
| | - Rinni Singh
- Department of Biochemistry, Lucknow University, Lucknow 226007, India
| | - Apul Goel
- Department of Urology, King George Medical University, Lucknow 226003, India
| | - Atin Singhai
- Department of Pathology, King George Medical University, Lucknow 226003, India
| | - Uday Pratap Singh
- Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Vinita Agrawal
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Minal Garg
- Department of Biochemistry, Lucknow University, Lucknow 226007, India
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22
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Kurogi K, Yoshihama M, Williams FE, Kenmochi N, Sakakibara Y, Suiko M, Liu MC. Identification of zebrafish steroid sulfatase and comparative analysis of the enzymatic properties with human steroid sulfatase. J Steroid Biochem Mol Biol 2019; 185:110-117. [PMID: 30118815 PMCID: PMC6289849 DOI: 10.1016/j.jsbmb.2018.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 07/11/2018] [Accepted: 08/08/2018] [Indexed: 11/19/2022]
Abstract
Steroid sulfatase (STS) plays an important role in the regulation of steroid hormones. Metabolism of steroid hormones in zebrafish has been investigated, but the action of steroid sulfatase remains unknown. In this study, a zebrafish sts was cloned, expressed, purified, and characterized in comparison with the orthologous human enzyme. Enzymatic assays demonstrated that similar to human STS, zebrafish Sts was most active in catalyzing the hydrolysis of estrone-sulfate and estradiol-sulfate, among five steroid sulfates tested as substrates. Kinetic analyses revealed that the Km values of zebrafish Sts and human STS differed with respective substrates, but the catalytic efficiency as reflected by the Vmax/Km appeared comparable, except for DHEA-sulfate with which zebrafish Sts appeared less efficient. While zebrafish Sts was catalytically active at 28 °C, the enzyme appeared more active at 37 °C and with similar Km values to those determined at 28 °C. Assays performed in the presence of different divalent cations showed that the activities of both zebrafish and human STSs were stimulated by Ca2+, Mg2+, and Mn2+, and inhibited by Zn+2 and Fe2+. EMATE and STX64, two known mammalian steroid sulafatase inhibitors, were shown to be capable of inhibiting the activity of zebrafish Sts. Collectively, the results obtained indicated that zebrafish Sts exhibited enzymatic characteristics comparable to the human STS, suggesting that the physiological function of STS may be conserved between zebrafish and humans.
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Affiliation(s)
- Katsuhisa Kurogi
- Department of Pharmacology, College of Pharmacy, University of Toledo Health Science Campus, Toledo, OH 43614, USA; Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Maki Yoshihama
- Department of Pharmacology, College of Pharmacy, University of Toledo Health Science Campus, Toledo, OH 43614, USA; Frontier Research Center, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Frederick E Williams
- Department of Pharmacology, College of Pharmacy, University of Toledo Health Science Campus, Toledo, OH 43614, USA
| | - Naoya Kenmochi
- Frontier Research Center, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Yoichi Sakakibara
- Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Masahito Suiko
- Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Ming-Cheh Liu
- Department of Pharmacology, College of Pharmacy, University of Toledo Health Science Campus, Toledo, OH 43614, USA.
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23
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Shimizu Y, Tamada S, Kato M, Takeyama Y, Fujioka M, Kakehashi A, Nakatani T, Wanibuchi H, Gi M. Steroid sulfatase promotes invasion through epithelial-mesenchymal transition and predicts the progression of bladder cancer. Exp Ther Med 2018; 16:4463-4470. [PMID: 30542396 PMCID: PMC6257456 DOI: 10.3892/etm.2018.6787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 08/17/2018] [Indexed: 11/11/2022] Open
Abstract
Androgen signal has been recently suggested to be associated with the progression of bladder cancer. Steroid sulfatase (STS) is a steroid sulfate activation enzyme, considered to be one of the key enzymes in the androgen signaling pathway. However, the role of STS in bladder cancer has not been elucidated. The purpose of the present study was to determine the clinical and functional significance of STS in bladder cancer. Immunohistochemical analysis of surgical specimens obtained by radical cystectomy (n=114) demonstrated that overexpression of STS was associated with the invasion of bladder cancer, as evidenced by the incidence of STS-positive cancers (11.5 and 37.1% in non-muscle invasive and muscle invasive bladder cancers, respectively; P=0.003). STS-positive cancer demonstrated shorter recurrence-free survival and cancer-specific survival (P=0.0027 and 0.0030, respectively). Furthermore, knockdown of STS significantly reduced cell migration and invasion capacities of bladder cancer cells (P<0.001 and P=0.005, respectively), accompanied by the upregulation of E-cadherin and downregulation of vimentin. In summary, the present study demonstrated that STS promotes the invasion capability of bladder cancer via regulation of the epithelial-mesenchymal transition, and may be a useful marker for predicting the progression of bladder cancers.
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Affiliation(s)
- Yasuomi Shimizu
- Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Satoshi Tamada
- Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Minoru Kato
- Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yuji Takeyama
- Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masaki Fujioka
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Anna Kakehashi
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tatsuya Nakatani
- Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Hideki Wanibuchi
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Min Gi
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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24
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Foster PA, Mueller JW. SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways. J Mol Endocrinol 2018; 61:T271-T283. [PMID: 29764919 DOI: 10.1530/jme-18-0086] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/15/2018] [Indexed: 12/18/2022]
Abstract
Sulfation and desulfation pathways represent highly dynamic ways of shuttling, repressing and re-activating steroid hormones, thus controlling their immense biological potency at the very heart of endocrinology. This theme currently experiences growing research interest from various sides, including, but not limited to, novel insights about phospho-adenosine-5'-phosphosulfate synthase and sulfotransferase function and regulation, novel analytics for steroid conjugate detection and quantification. Within this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including chronic inflammatory diseases and steroid-dependent cancers.
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Affiliation(s)
- Paul A Foster
- Institute of Metabolism and Systems Research (IMSR)University of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK
| | - Jonathan Wolf Mueller
- Institute of Metabolism and Systems Research (IMSR)University of Birmingham, Birmingham, UK
- Centre for EndocrinologyDiabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK
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25
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Potter BVL. SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects. J Mol Endocrinol 2018; 61:T233-T252. [PMID: 29618488 DOI: 10.1530/jme-18-0045] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 04/04/2018] [Indexed: 12/13/2022]
Abstract
Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl O-sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the Pseudomonas aeruginosa arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.
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Affiliation(s)
- Barry V L Potter
- Medicinal Chemistry & Drug DiscoveryDepartment of Pharmacology, University of Oxford, Oxford, UK
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26
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Yan HB, Zhang Y, Cen JM, Wang X, Gan BL, Huang JC, Li JY, Song QH, Li SH, Chen G. Expression of microRNA-99a-3p in Prostate Cancer Based on Bioinformatics Data and Meta-Analysis of a Literature Review of 965 Cases. Med Sci Monit 2018; 24:4807-4822. [PMID: 29997385 PMCID: PMC6069561 DOI: 10.12659/msm.908057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND microRNAs (miRNAs) have a role as biomarkers in human cancer. The aim of this study was to use bioinformatics data, and review of cases identified from the literature, to investigate the role of microRNA-99a-3p (miR-99a-3p) in prostate cancer, including the identification of its target genes and signaling pathways. MATERIAL AND METHODS Meta-analysis from a literature review included 965 cases of prostate cancer. Bioinformatics databases interrogated for miR-99a-3p in prostate cancer included The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and ArrayExpress. Twelve computational predictive algorithms were developed to integrate miR-99a-3p target gene prediction data. Bioinformatics analysis data from Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analysis were used investigate the possible pathways and target genes for miR-99a-3p in prostate cancer. RESULTS TCGA data showed that miR-99a was down-regulated in prostate cancer when compared with normal prostate tissue. Receiver-operating characteristic (ROC) curve area under the curve (AUC) for miR-99a-3p was 0.660 (95% CI, 0.587-0.732) or a moderate level of discriminations. Pathway analysis showed that miR-99a-3p was associated with the Wnt and vascular endothelial growth factor (VEGF) signaling pathways. The PPP3CA and HYOU1 genes, selected from the PPI network, were highly expressed in prostate cancer tissue compared with normal prostate tissue, and negatively correlated with the expression of miR-99a-3p. CONCLUSIONS In prostate cancer, miR-99a-3p expression was associated with the Wnt and VEGF signaling pathways, which might inhibit the expression of PPP3CA or HYOU1.
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Affiliation(s)
- Hai-Biao Yan
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Yu Zhang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Jie-Mei Cen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Xiao Wang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, Shandong, China (mainland)
| | - Bin-Liang Gan
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Jia-Cheng Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Jia-Yi Li
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Qian-Hui Song
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Sheng-Hua Li
- Department of Urology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
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27
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Meirson T, Gil-Henn H. Targeting invadopodia for blocking breast cancer metastasis. Drug Resist Updat 2018; 39:1-17. [PMID: 30075834 DOI: 10.1016/j.drup.2018.05.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/04/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022]
Abstract
Dissemination of cancer cells from the primary tumor and their spread to distant sites of the body is the leading cause of mortality in metastatic cancer patients. Metastatic cancer cells invade surrounding tissues and blood vessels by forming F-actin-rich protrusions known as invadopodia, which degrade the extracellular matrix and enable invasion of tumor cells through it. Invadopodia have now been observed in vivo, and recent evidence demonstrates direct molecular links between assembly of invadopodia and cancer metastasis in both mouse models and in human patients. While significant progress has been achieved in the last decade in understanding the molecular mechanisms and signaling pathways regulating invadopodia formation and function, the application of this knowledge to development of prognostic and therapeutic approaches for cancer metastasis has not been discussed before. Here, we provide a detailed overview of current prognostic markers and tests for cancer metastasis and discuss their advantages, disadvantages, and their predicted efficiency. Using bioinformatic patient database analysis, we demonstrate, for the first time, a significant correlation between invadopodia-associated genes to breast cancer metastasis, suggesting that invadopodia could be used as both a prognostic marker and as a therapeutic target for blocking cancer metastasis. We include here a novel network interaction map of invadopodia-associated proteins with currently available inhibitors, demonstrating a central role for the recently identified EGFR-Pyk2-Src-Arg-cortactin invadopodial pathway, to which re-purposing of existent inhibitors could be used to block breast cancer metastasis. We then present an updated overview of current cancer-related clinical trials, demonstrating the negligible number of trials focusing on cancer metastasis. We also discuss the difficulties and complexity of performing cancer metastasis clinical trials, and the possible development of anti-metastasis drug resistance when using a prolonged preventive treatment with invadopodia inhibitors. This review presents a new perspective on invadopodia-mediated tumor invasiveness and may lead to the development of novel prognostic and therapeutic approaches for cancer metastasis.
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Affiliation(s)
- Tomer Meirson
- Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel; Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Hava Gil-Henn
- Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel.
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28
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Li C, Liu J, Zhang Q, Cui K, Ge Q, Wang C, Chen Z. Upregulation of E‑cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting β-catenin/TCF target genes. Int J Oncol 2018; 52:1815-1826. [PMID: 29620261 PMCID: PMC5919711 DOI: 10.3892/ijo.2018.4346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 03/21/2018] [Indexed: 01/03/2023] Open
Abstract
Low expression levels of E-cadherin are correlated with poor prognosis in patients with bladder cancer (BCa). A small activating RNA (saRNA) targeting a specific promoter region can activate gene expression. In the present study, two small double-stranded RNAs (dsRNAs) targeting the promoter region of human E-cadherin were designed and synthesized, and the regulatory role of saRNAs in E-cadherin expression was investigated. The results of reverse transcription-quantitative polymerase chain reaction and western blotting demonstrated that transfection of dsEcad-346 into the BCa cell lines T24 and 5637 significantly activated E-cadherin expression. Furthermore, transfection of dsEcad-346 and miR-373 induced cell cycle arrest in G0/G1 phase, promoted apoptosis and significantly inhibited migration and invasion of BCa cells. Results of immunofluorescence and western blotting indicated that β-catenin was redistributed from the nucleus to the cell membrane following transfection of dsEcad-346 and miR-373. Additionally, the expression of β-catenin/T-cell factor complex (TCF) target genes (c-MYC, matrix metallopeptidase 2, cyclin D1) was suppressed following transfection of BCa cells with saRNA. Silencing of E-cadherin expression blocked the inhibitory effect of dsEcad-346 and miR-373 on BCa cells. In conclusion, a novel designed dsEcad-346 can activate the expression of E-cadherin in BCa cells. saRNA-mediated activation of E-cadherin expression inhibited the growth and metastasis of BCa cells by promoting the redistribution of β-catenin from nucleus to cell membrane and inhibiting the β-catenin/TCF target genes.
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Affiliation(s)
- Chuanchang Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Jiaxuan Liu
- Department of Pathology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Qingsong Zhang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Kai Cui
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Qiangqiang Ge
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Chenghe Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhong Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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29
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Terakawa T, Katsuta E, Yan L, Turaga N, McDonald KA, Fujisawa M, Guru KA, Takabe K. High expression of SLCO2B1 is associated with prostate cancer recurrence after radical prostatectomy. Oncotarget 2018; 9:14207-14218. [PMID: 29581838 PMCID: PMC5865664 DOI: 10.18632/oncotarget.24453] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 02/01/2018] [Indexed: 01/22/2023] Open
Abstract
Solute carrier organic anion (SLCO) gene families encode organic anion transport proteins, which are transporters that up-take a number of substrates including androgens. Among them, high expression of SLCO2B1 is known to associate with the resistance to androgen deprivation therapy in prostate cancer (PCa). We hypothesized that high expression of SLCO genes enhances PCa progression by promoting the influx of androgen. Here, we demonstrated the impact of the expression levels of SLCO2B1 on prognosis in localized PCa after radical prostatectomy (RP) utilizing 494 PCa cases in The Cancer Genome Atlas (TCGA). SLCO2B1 high expression group showed significantly worse Disease-free survival (DFS) after RP (p = 0.001). The expression level of SLCO2B1 was significantly higher in advanced characteristics including Gleason Score (GS ≤ 6 vs GS = 7; p = 0.047, GS = 7 vs GS ≥ 8; p = 0.002), pathological primary tumor (pT2 vs pT3/4; p < 0.001), and surgical margin status (positive vs negative; p = 0.013), respectively. There was a significant difference in DFS between these two groups only in GS ≥ 8 patients (p = 0.006). Multivariate analysis demonstrated that only SLCO2B1 expression level was an independent predictor for DFS after RP in GS ≥ 8. SLCO2B1 high expressed tumors in GS ≥ 8 not only enriched epithelial mesenchymal transition (EMT) related gene set, (p = 0.027), as well as Hedgehog (p < 0.001), IL-6/JAK/STAT3 (p < 0.001), and K-ras signaling gene sets (p < 0.001), which are known to promote EMT, but also showed higher expression of EMT related genes, including N-cadherin (p = 0.024), SNAIL (p = 0.001), SLUG (p = 0.001), ZEB-1 (p < 0.001) and Vimentin (p < 0.001). In conclusion, PCa with high expression of SLCO2B1 demonstrated worse DFS, which might be due to accelerated EMT.
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Affiliation(s)
- Tomoaki Terakawa
- Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Eriko Katsuta
- Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, NY, USA
| | - Nitesh Turaga
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, NY, USA
| | - Kerry-Ann McDonald
- Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Khurshid A Guru
- Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Surgery, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, The State University of New York Buffalo, NY, USA.,Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.,Department of Surgery, Yokohama City University, Yokohama, Japan.,Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Maolakuerban N, Azhati B, Tusong H, Abula A, Yasheng A, Xireyazidan A. MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1. Cancer Biol Ther 2018; 19:282-291. [PMID: 29394133 DOI: 10.1080/15384047.2017.1394551] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In this study, we investigated the mechanism of miR-200c-3p and SLC6A1 in regulating cell activity of clear cell renal cell carcinoma (CCRCC). The mRNA and miRNA expressions of tissue specimens were analyzed by CapitalBio Corporation (Beijing, China). The expression of SLC6A1 in CCRCC cells was examined through qRT-PCR and western blot. The migration and invasion ability of 786-O cells was testified by transwell assay after transfected. 786-O cell proliferation ability was detected by MTT assay. Dual luciferase reporter assay verified the association between SLC6A1 and miR-200c-3p. SLC6A1 was high expressed and miR-200c-3p was low expressed in CCRCC tissues and cells. Besides, lower SLC6A1 expression indicated longer survival time and higher survival rate. MiR-200c-3p could directly target at SLC6A1 and reduce its expression. MiR-200c-3p inhibited the proliferation, migration and invasion in 786-O cells by down-regulating SLC6A1 expression. The results suggested that the miR-200c-3p served as a suppressor for CCRCC via down-regulating SLC6A1.
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Affiliation(s)
- Naibijiang Maolakuerban
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
| | - Baihetiya Azhati
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
| | - Hamulati Tusong
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
| | - Asimujiang Abula
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
| | - Anniwaer Yasheng
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
| | - Ayiding Xireyazidan
- a Department of Urology , the First Affiliated Hospital of Xinjiang Medical University , 830054 Urumchi , Xinjiang , China
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Li H, Lin Z, Bai Y, Chi X, Fu H, Sun R, Liu M, Liu X, Chen L, Shao S. Sinomenine inhibits ovarian cancer cell growth and metastasis by mediating the Wnt/β-catenin pathway via targeting MCM2. RSC Adv 2017. [DOI: 10.1039/c7ra10057d] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Sinomenine (SIN), an isoquinoline isolated from the Chinese medicinal plantSinomenium acutum, is well known for its curative effect on rheumatic and arthritic diseases.
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Affiliation(s)
- Huimin Li
- Department of Histology and Embryology
- Dalian Medical University
- Dalian
- China
| | - Zhikun Lin
- The First Affiliated Hospital of Dalian Medical University
- Dalian
- China
| | - Yuxin Bai
- Department of Histology and Embryology
- Dalian Medical University
- Dalian
- China
| | - Xinming Chi
- Key Laboratory of Proteomics
- Dalian Medical University
- Dalian
- China
| | - Hailu Fu
- Department of Histology and Embryology
- Dalian Medical University
- Dalian
- China
| | - Rui Sun
- The Second Affiliated Hospital of Dalian Medical University
- Dalian
- China
| | - Meizi Liu
- The First Affiliated Hospital of Dalian Medical University
- Dalian
- China
| | - Xuan Liu
- Department of Histology and Embryology
- Dalian Medical University
- Dalian
- China
| | - Liying Chen
- Department of Histology and Embryology
- Dalian Medical University
- Dalian
- China
| | - Shujuan Shao
- Key Laboratory of Proteomics
- Dalian Medical University
- Dalian
- China
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