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Wang W, Lu Y, Qin GM, Ni LF, Xu BX, Liu CF, Yu BF, Wang HL, Pang M. LncRNA RP11-297P16.4 Promotes the Invasion and Metastasis of Non-Small-Cell Lung Carcinoma by Targeting the miR-145-5p/MMP-2/9 Axis. Biomedicines 2025; 13:617. [PMID: 40149594 PMCID: PMC11940468 DOI: 10.3390/biomedicines13030617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/25/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Long noncoding RNAs (lncRNAs) participate in the occurrence and development of non-small-cell lung carcinoma (NSCLC). But for certain lncRNAs, their effects on NSCLC remain unclear. This work discovered that lncRNA RP11-297P16.4 is elevated in NSCLC. Methods: LncRNA RP11-297P16.4 expression within LUAD tissues and cells was measured through RT-qPCR and Western blot. To assess the role of the lncRNA RP11-297P16.4 in NSCLC, gain- or loss-of-function experiments were conducted using an NSCLC mouse tumor model. Results: Silencing of the lncRNA RP11-297P16.4 inhibited the NSCLC cell line invasion and migration potential, but re-expression of the lncRNA RP11-297P16.4 had the opposite effect. A luciferase reporter confirmed that the lncRNA RP11-297P16.4 functions as a competitive endogenous RNA (ceRNA) through the sponge of miR-145-5p. The expression of lncRNA RP11-297P16.4 was negatively correlated to the level of miR-145-5p in NSCLC cells, which sponged miR-145-5p and suppressed tumor cell migration and invasion by targeting matrix metalloproteinase 2 (MMP-2) and MMP-9. Conclusions: Our findings suggested that the lncRNA RP11-297P16.4/miR-145-5p/MMP-2/9 regulatory axis is the key pathway for mediating the migration and invasion of NSCLC.
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Affiliation(s)
- Wei Wang
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Yu Lu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Guang-Mei Qin
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Lin-Feng Ni
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Bai-Xue Xu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Chao-Feng Liu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Bao-Feng Yu
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Hai-Long Wang
- School of Basic Medical Sciences, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong 030600, China; (W.W.); (Y.L.); (G.-M.Q.); (L.-F.N.); (B.-X.X.); (C.-F.L.); (B.-F.Y.)
| | - Min Pang
- NHC Key Laboratory of Pneumoconiosis, Shanxi Province Key Laboratory of Respiratory Disease, Department of Pulmonary and Critical Care Medicine, The First Hospital, Shanxi Medical University, Taiyuan 030001, China
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Sharma B, Shekhar H, Sahu A, Haque S, Kaur D, Tuli HS, Sharma U. Deciphering the anticancer potential of thymoquinone: in-depth exploration of the potent flavonoid from Nigella sativa. Mol Biol Rep 2025; 52:268. [PMID: 40016603 DOI: 10.1007/s11033-025-10375-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/20/2025] [Indexed: 03/01/2025]
Abstract
Since its first written description around 3000 BC until the present day, cancer has stood as a leading global cause of death, claiming the lives of 1 in 6 individuals. Due to its widespread impact and lethality, it remains one of the most explored yet most challenging disease for the global scientific community. Throughout history, various plant extracts have been used in treating numerous diseases, including cancer. These natural extracts are regaining attention due to their therapeutic benefits and lesser side effects. Thymoquinone, chemically 2-isopropyl-5-methylbenzo-1,4-quinone, constitutes the primary bioactive component of the plant Nigella sativa. Extensive research across in vivo, in vitro models, and clinical trials has revealed Thymoquinone's noteworthy therapeutic potential against cancer. Thymoquinone has shown promising anti-cancer activity in various cancers including breast cancer, lung cancer, prostate cancer, colorectal cancer, cervical cancer, pancreatic cancer, gastric cancer and blood cancers. However, there are challenges such as limited clinical trials, low bioavailability, and the need for more research to understand its long-term safety and effectiveness. This article provides a comprehensive and thorough review of thymoquinone, covering its effectiveness across various malignancies, the molecular signalling pathways it influences, and its role in triggering apoptosis and inhibiting inflammation, angiogenesis, and metastasis. Additionally, the review includes a thorough examination of thymoquinone's pharmacokinetics and safety, making it the first of its kind in its comprehensiveness.
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Affiliation(s)
- Bunty Sharma
- Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, Uttarakhand, India
| | - Himanshu Shekhar
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Anidrisha Sahu
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, 45142, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, 1102 2801, Lebanon
| | - Damandeep Kaur
- University Centre for Research & Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, Punjab, 140413, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207, India
| | - Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, 151001, India.
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Göbel G, Müller F, Talke A, Ahnert U, Lisdat F. Qualitative and quantitative protease activity tests based on protein degradation in three-dimensional structures. Bioelectrochemistry 2024; 160:108775. [PMID: 39003949 DOI: 10.1016/j.bioelechem.2024.108775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/27/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024]
Abstract
The pattern of the activity of proteases is related to distinct physiological states of living organisms. Often activity changes of a certain protease can be assigned to a specific disease. Hence, they are useful biomarkers and a simple and fast determination method of their activity could be a valuable tool for the efficient monitoring of numerous diseases. Here, two different methods for the qualitative and quantitative determination of protease activity are demonstrated using the model system of proteinase K. The first test system is based on a protein-modified and colored 3D silica structure that changes color when exposed to the enzyme. This method has also been used for the detection of matrix metallo-protease 2 (MMP2) with gelatine as protease substrate on the plates. The second detection system uses the decrease in the voltammetric signal of a cytochrome c/DNA multilayer electrode after incubation with a protease to quantitatively determine its proteolytic activity. While activities down to 0.15 U/ml can be detected with the first method, the second one provides detection limits of about 0.03U/ml (for proteinase K.) The functionality of both systems can be demonstrated and ways for further enhancement of sensitivity have been elucidated.
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Affiliation(s)
- G Göbel
- Biosystems Technology, Institute of Life Sciences and Biomedical Technologies, Technical University Wildau, Germany.
| | - F Müller
- Biosystems Technology, Institute of Life Sciences and Biomedical Technologies, Technical University Wildau, Germany
| | - A Talke
- BioTeZ Berlin Buch GmbH, Berlin, Germany
| | - U Ahnert
- BioTeZ Berlin Buch GmbH, Berlin, Germany
| | - F Lisdat
- Biosystems Technology, Institute of Life Sciences and Biomedical Technologies, Technical University Wildau, Germany.
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Lee CJ, Jang TY, Jeon SE, Yun HJ, Cho YH, Lim DY, Nam JS. The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression. Nat Commun 2024; 15:10422. [PMID: 39613801 DOI: 10.1038/s41467-024-54920-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024] Open
Abstract
The dynamic alteration of the tumor microenvironment (TME) serves as a driving force behind the progression and metastasis of colorectal cancer (CRC). Within the intricate TME, a pivotal player is the extracellular matrix (ECM), where modifications in components, degradation, and stiffness are considered critical factors in tumor development. In this study, we find that the membrane glycoprotein dysadherin directly targets matrix metalloprotease 9 (MMP9), initiating ECM remodeling within the TME and amplifying cancer progression. Mechanistically, the dysadherin/MMP9 axis not only enhances CRC cell invasiveness and ECM proteolytic activity but also activates cancer-associated fibroblasts, orchestrating the restructuring of the ECM through the synthesis of its components in human CRC cells, patient samples, and mouse models. Notably, disruption of ECM reorganization by dysadherin knockout results in a discernible reduction in the immunosuppressive and proangiogenic milieu in a humanized mouse model. Intriguingly, these effects are reversed upon the overexpression of MMP9, highlighting the intricate and pivotal role of the dysadherin/MMP9 axis in shaping the development of a malignant TME. Therefore, our findings not only highlight that dysadherin contributes to CRC progression by influencing the TME through ECM remodeling but also suggest that dysadherin may be a potential therapeutic target for CRC.
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Affiliation(s)
- Choong-Jae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Tae-Young Jang
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - So-El Jeon
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Hyeon-Ji Yun
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Yeong-Hoon Cho
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Da-Ye Lim
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jeong-Seok Nam
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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Zhang M, He M, Bai L, Du F, Xie Y, Li B, Zhang Y. CircMALAT1 promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma via the miR-512-5p/VCAM1 axis. Acta Biochim Biophys Sin (Shanghai) 2024; 57:223-236. [PMID: 39463204 DOI: 10.3724/abbs.2024185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2024] Open
Abstract
Circular RNAs play a pivotal role in the progression of various cancers. In our previous study, we observed high expression of the circRNA MALAT1 (cMALAT1) in intrahepatic cholangiocarcinoma (ICC) cells co-incubated with activated hepatic stellate cells. This study is designed to explore the roles of cMALAT1 and the underlying mechanisms in ICC. We find that cMALAT1 significantly facilitates the progression of ICC both in vitro and in vivo. The binding between cMALAT1 and miR-512-5p is subsequently confirmed through RNA pull-down experiments. As anticipated, the application of miR-512-5p mimics noticeably reverses the cMALAT1 overexpression-induced malignant phenotypes of ICC cells. Furthermore, VCAM1 is identified as a downstream gene of the cMALAT1/miR-512-5p axis. Importantly, silencing of VCAM1 not only effectively suppresses the malignant phenotypes of ICC cells but also significantly impairs the functions of cMALAT1. Our study reveals that cMALAT1 promotes the progression of ICC by competitively binding to VCAM1 mRNA with miR-512-5p, leading to the upregulation of VCAM1 expression and the activation of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Meixia Zhang
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Mingyan He
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Liangliang Bai
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Fan Du
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Yingping Xie
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Bimin Li
- Department of Gastroenterology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Yuming Zhang
- Department of Surgery, People's Hospital of Nanchang Economic and Technological Development Zone, Nanchang 330013, China
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Siddhartha R, Goel A, Singhai A, Garg M. Matrix Metalloproteinases -2 and -9, Vascular Endothelial Growth Factor, Basic Fibroblast Growth Factor and CD105- Micro-Vessel Density are Predictive Markers of Non-Muscle Invasive Bladder Cancer and Muscle Invasive Bladder Cancer Subtypes. Biochem Genet 2024. [DOI: 10.1007/s10528-024-10921-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 09/15/2024] [Indexed: 01/12/2025]
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7
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Holm H, Magnusson M, Jujić A, Lagrange J, Bozec E, Lamiral Z, Bresso E, Huttin O, Baudry G, Monzo L, Rossignol P, Zannad F, Girerd N. Association of ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology - the STANISLAS cohort. Eur J Heart Fail 2024. [PMID: 39189882 DOI: 10.1002/ejhf.3411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/28/2024] Open
Abstract
AIMS Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals. METHODS AND RESULTS In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF-related proteins with non-invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end-systolic elastance (Ees). Among the 32 tested proteins, fatty acid-binding protein adipocyte 4, interleukin-6, growth differentiation factor 15, matrix metalloproteinase (MMP)-1, and MMP-9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP-2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were negatively associated. In multivariable models, only MMP-2 and NT-proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT-proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup. CONCLUSION Elevated MMP-2 and NT-proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload.
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Affiliation(s)
- Hannes Holm
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden
| | - Martin Magnusson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Amra Jujić
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden
| | - Jérémy Lagrange
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Erwan Bozec
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Zohra Lamiral
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Emmanuel Bresso
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Olivier Huttin
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Guillaume Baudry
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Luca Monzo
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Nicolas Girerd
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-1433, and Inserm, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
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Liang S, Li L, Guo Z, Sun H, Yang Y. Co-expression of CD44v6 and MMP2 predicts lung metastasis and unfavorable prognosis in osteosarcoma. Future Oncol 2024; 20:1799-1806. [PMID: 39011948 PMCID: PMC11485780 DOI: 10.1080/14796694.2024.2370234] [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: 02/12/2024] [Accepted: 06/17/2024] [Indexed: 07/17/2024] Open
Abstract
Aim: To evaluate the prognostic significance of CD44 variant v6 (CD44v6) and matrix metalloproteinases 2 (MMP2) expression in patients with surgically resected osteosarcoma.Methods: CD44v6 and MMP2 expression were immunohistochemically detected in 113 primary osteosarcoma patients at our institute between 2001 and 2019.Results: Both CD44v6 and MMP2 were independent predictors for metastasis-free and overall survival. An extended predictive range and improved sensitivity were observed when the combined effects of CD44v6 and MMP2 were considered. Specifically, patients with CD44v6+ and MMP2+ expression were more susceptible to lung metastasis and exhibited the poorest survival rates compared with the other groups.Conclusion: The combination of CD44v6 and MMP2 may serve as a precise prognostic indicator for predicting metastatic progression and survival outcomes in patients with osteosarcoma.
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Affiliation(s)
- Shoulei Liang
- Department of orthopedic, The Second Hospital of Tangshan, No.21, Jianshe North Road, Tangshan063000, China
| | - Liang Li
- Department of orthopedic, The Second Hospital of Tangshan, No.21, Jianshe North Road, Tangshan063000, China
| | - Zhiliang Guo
- Department of orthopedic, The Second Hospital of Tangshan, No.21, Jianshe North Road, Tangshan063000, China
| | - Haijing Sun
- Department of orthopedic, The Second Hospital of Tangshan, No.21, Jianshe North Road, Tangshan063000, China
| | - Yan Yang
- Department of orthopedic, The Second Hospital of Tangshan, No.21, Jianshe North Road, Tangshan063000, China
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Sharma U, Sharma B, Mishra A, Sahu A, Mathkor DM, Haque S, Raina D, Ramniwas S, Gupta M, Tuli HS. Ononin: A comprehensive review of anticancer potential of natural isoflavone glycoside. J Biochem Mol Toxicol 2024; 38:e23735. [PMID: 38773908 DOI: 10.1002/jbt.23735] [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: 02/21/2024] [Revised: 04/03/2024] [Accepted: 05/09/2024] [Indexed: 05/24/2024]
Abstract
Cancer is one of the major causes of death worldwide, with more than 10 million deaths annually. Despite tremendous advances in the health sciences, cancer continues to be a substantial global contributor to mortality. The current treatment methods demand a paradigm shift that not only improves therapeutic efficacy but also minimizes the side effects of conventional medications. Recently, an increased interest in the potential of natural bioactive compounds in the treatment of several types of cancer has been observed. Ononin, also referred to as formononetin-7-O-β-d-glucoside, is a natural isoflavone glycoside, derived from the roots, stems, and rhizomes of various plants. It exhibits a variety of pharmacological effects, including Antiangiogenic, anti-inflammatory, antiproliferative, proapoptotic, and antimetastatic activities. The current review presents a thorough overview of sources, chemistry, pharmacokinetics, and the role of ononin in affecting various mechanisms involved in cancer. The review also discusses potential synergistic interactions with other compounds and therapies. The combined synergistic effect of ononin with other compounds increased the efficacy of treatment methods. Finally, the safety studies, comprising both in vitro and in vivo assessments of ononin's anticancer activities, are described.
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Affiliation(s)
- Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, India
| | - Bunty Sharma
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, India
| | - Ambrish Mishra
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, India
| | - Anidrisha Sahu
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bhatinda, India
| | - Darin M Mathkor
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
| | - Deepika Raina
- School of Pharmacy, Graphic Era Hill University, Dehradun, India
| | - Seema Ramniwas
- University Centre for Research & Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, India
| | - Madhu Gupta
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Hardeep S Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, India
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Huang YP, Yeh CA, Ma YS, Chen PY, Lai KC, Lien JC, Hsieh WT. PW06 suppresses cancer cell metastasis in human pancreatic carcinoma MIA PaCa-2 cells via the inhibitions of p-Akt/mTOR/NF-κB and MMP2/MMP9 signaling pathways in vitro. ENVIRONMENTAL TOXICOLOGY 2024; 39:2768-2781. [PMID: 38264921 DOI: 10.1002/tox.24143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/14/2023] [Accepted: 01/06/2024] [Indexed: 01/25/2024]
Abstract
PW06 [(E)-3-(9-ethyl-9H-carbazol-3-yl)-1-(2,5-dimethoxyphenyl) prop-2-en-1-one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1-0.8 μM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa-2 cells in vitro. Wound healing assay shows PW06 at 0.2 μM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 μM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1-0.2 μM) suppressed the cell migration (decreased 26.67-35.42%) and invasion (decreased 48.51-68.66%). Atomic force microscopy assay shows PW06 (0.2 μM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p-JNK, p-ERK, and p-p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/β, and E-cadherin. Nevertheless, results also show PW06 decreased p-Akt, mTOR, NF-κB, p-GSK3β, β-catenin, Snail, N-cadherin, and vimentin in MIA PaCa-2 cells. The confocal laser microscopy examination shows PW06 increased E-cadherin but decreased vimentin in MIA PaCa-2 cells. Together, our findings strongly suggest that PW06 inhibited the p-Akt/mTOR/NF-κB/MMPs pathways, increased E-cadherin, and decreased N-cadherin/vimentin, suppressing the migration and invasion in MIA PaCa-2 cells in vitro.
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Affiliation(s)
- Yi-Ping Huang
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chun-An Yeh
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Yi-Shih Ma
- School of Chinese Medicine for Post-Baccalaureate, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Chinese Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Po-Yuan Chen
- Department of Biological Science and Technology, College of Life Science, China Medical University, Taichung, Taiwan
| | - Kuang-Chi Lai
- Department of Medical Laboratory Science and Biotechnology, College of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Department of Surgery, School of Medicine, China Medical University, Taichung, Taiwan
| | - Jin-Cherng Lien
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Wen-Tsong Hsieh
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Pharmacology, China Medical University, Taichung, Taiwan
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11
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Rezaei A, Moqadami A, Khalaj-Kondori M, Feizi MAH. Minocycline induced apoptosis and suppressed expression of matrix metalloproteinases 2 and 9 in the breast cancer MCF-7 cells. Mol Biol Rep 2024; 51:463. [PMID: 38551800 DOI: 10.1007/s11033-024-09380-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 02/26/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND In women, breast cancer is the second most frequent type of cancer. Looking for new and effective cancer-specific therapies with little to no adverse effects on healthy cells is critical. OBJECTIVE Minocycline, a second-generation tetracycline, has shown anticancer effects by targeting multiple pathways in various cancers. This study aimed to determine minocycline effects on the cell proliferation, apoptosis, and invasion of the human MCF-7 cells. METHODS MTT assay was used to evaluate the cytotoxicity of minocycline on the cells. Flow cytometry was performed to investigate the induction of apoptosis and the cell cycle progression. The expression levels of apoptotic and migration proteins and genes were assessed by western blotting and qRT-PCR. The scratch test was performed to evaluate the anti-migration effect of the drug. RESULTS The results indicated that the IC50 value of minocycline for MCF-7 cells was 36.10 µM. Minocycline treatment caused sub-G1 cell accumulation, indicating a significant apoptotic effect on the MCF-7 cells. Annexin-V/PI staining revealed a significant rise in early and late apoptotic cell percentages. Minocycline up-regulated Bax and Caspase-3 expression and down-regulated Bcl-2 and Pro-Cas3. The scratch test revealed significant anti-migration effects for minocycline. Furthermore, it caused down-regulation of MMP-2 and MMP-9 in a concentration-dependent method. CONCLUSION These findings further confirmed the anticancer effect of minocycline and highlighted that minocycline maybe considered as potential therapeutic agent for breast cancer treatment.
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Affiliation(s)
- Abedeh Rezaei
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Amin Moqadami
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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12
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Hey S, Linder S. Matrix metalloproteinases at a glance. J Cell Sci 2024; 137:jcs261898. [PMID: 38236162 DOI: 10.1242/jcs.261898] [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] [Indexed: 01/19/2024] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that belong to the group of endopeptidases or matrixins. They are able to cleave a plethora of substrates, including components of the extracellular matrix and cell-surface-associated proteins, as well as intracellular targets. Accordingly, MMPs play key roles in a variety of physiological and pathological processes, such as tissue homeostasis and cancer cell invasion. MMP activity is exquisitely regulated at several levels, including pro-domain removal, association with inhibitors, intracellular trafficking and transport via extracellular vesicles. Moreover, the regulation of MMP activity is currently being rediscovered for the development of respective therapies for the treatment of cancer, as well as infectious, inflammatory and neurological diseases. In this Cell Science at a Glance article and the accompanying poster, we present an overview of the current knowledge regarding the regulation of MMP activity, the intra- and extra-cellular trafficking pathways of these enzymes and their diverse groups of target proteins, as well as their impact on health and disease.
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Affiliation(s)
- Sven Hey
- Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Stefan Linder
- Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
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13
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Somasundaram DB, Aravindan S, Major R, Natarajan M, Aravindan N. MMP-9 reinforces radiation-induced delayed invasion and metastasis of neuroblastoma cells through second-signaling positive feedback with NFκB via both ERK and IKK activation. Cell Biol Toxicol 2023; 39:1053-1076. [PMID: 34626302 DOI: 10.1007/s10565-021-09663-4] [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: 03/09/2021] [Accepted: 09/28/2021] [Indexed: 10/20/2022]
Abstract
Neuroblastoma (NB) progression is branded with hematogenous metastasis and frequent relapses. Despite intensive multimodal clinical therapy, outcomes for patients with progressive disease remain poor, with negligible long-term survival. Therefore, understanding the acquired molecular rearrangements in NB cells with therapy pressure and developing improved therapeutic strategies is a critical need to improve the outcomes for high-risk NB patients. We investigated the rearrangement of MMP9 in NB with therapy pressure, and unveiled the signaling that facilitates NB evolution. Radiation-treatment (RT) significantly increased MMP9 expression/activity, and the induced enzyme activity was persistently maintained across NB cell lines. Furthermore, RT-triggered NFκB transcriptional activity and this RT-induced NFκB were required/adequate for MMP9 maintenance. RT-triggered NFκB-dependent MMP9 actuated a second-signaling feedback to NFκB, facilitating a NFκB-MMP9-NFκB positive feedback cycle (PFC). Critically, MMP9-NFκB feedback is mediated by MMP9-dependent activation of IKKβ and ERK phosphotransferase activity. Beyond its tumor invasion/metastasis function, PFC-dependent MMP9 lessens RT-induced apoptosis and favors survival pathway through the activation of NFκB signaling. In addition, PFC-dependent MMP9 regulates 19 critical molecular determinants that play a pivotal role in tumor evolution. Interestingly, seven of 19 genes possess NFκB-binding sites, demonstrating that MMP9 regulates these molecules by activating NFκB. Collectively, these data suggest that RT-triggered NFκB-dependent MMP9 actuates feedback to NFκB though IKKβ- and ERK1/2-dependent IκBα phosphorylation. This RT-triggered PFC prompts MMP9-dependent survival advantage, tumor growth, and dissemination. Targeting therapy-pressure-driven PFC and/or selective inhibition of MMP9 maintenance could serve as promising therapeutic strategies for treatment of progressive NB.
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Affiliation(s)
- Dinesh Babu Somasundaram
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, BMSB 311, 940 Stanton L. Young Boulevard, Oklahoma City, OK, 73104, USA
| | | | - Ryan Major
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, BMSB 311, 940 Stanton L. Young Boulevard, Oklahoma City, OK, 73104, USA
| | - Mohan Natarajan
- Department of Pathology & Laboratory Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA
| | - Natarajan Aravindan
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, BMSB 311, 940 Stanton L. Young Boulevard, Oklahoma City, OK, 73104, USA.
- Stephenson Cancer Center, Oklahoma City, OK, USA.
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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14
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Korenevsky AV, Gert TN, Berezkina ME, Sinyavin SA, Mikhailova VA, Markova KL, Simbirtsev AS, Selkov SA, Sokolov DI. Protein Fractions of Natural Killer Cell Lysates Affect the Phenotype, Proliferation and Migration of Endothelial Cells in vitro. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022070171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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15
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Chelerythrine Inhibits Stemness of Cancer Stem-Like Cells of Osteosarcoma and PI3K/AKT/mTOR Signal. JOURNAL OF ONCOLOGY 2022; 2022:6435431. [PMID: 36131794 PMCID: PMC9484924 DOI: 10.1155/2022/6435431] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022]
Abstract
Chelerythrine (CHE) is widely found in many herbs and is the main alkaloid constituent of Toddalia asiatica (L.) LAM. It has been proved to exert remarkable antitumor, antifungal, anti-inflammatory, and antiparasitic effects. In osteosarcoma, CHE is reported to inhibit proliferation and promote apoptosis. However, the effect of CHE on cancer stem-like cells (CSCs), which contribute to metastasis and recurrence in osteosarcoma, is still largely unknown. In this study, we investigated the effects of CHE on the stemness and malignant behaviors of CSCs derived from osteosarcoma cells. CSCs were enriched by culturing in serum-free medium. The effects of CHE on stemness were measured by detecting stemness factors and sphere formation ability. The effects of CHE on chemosensitivity to doxorubicin and MTX were measured by Annexin V-FITC/PI double staining. The effects of CHE on CSC malignancy were measured by performing CCK-8, colony formation, tumor formation in soft agar, migration, and invasion assays. We first enriched CSCs from osteosarcoma cells, which were characterized by upregulated stemness markers, including Oct4, Nanog, and Nestin. The addition of CHE clearly decreased malignant behaviors, including colony formation, tumor formation in soft agar, migration, and invasion. CHE also inhibited stemness and thus induced the failure of sphere formation. Moreover, CHE promoted apoptosis induced by chemo agents, including doxorubicin (DOX) and methotrexate (MTX). After CHE treatment, the protein expression of MMP-2/9 was significantly decreased, potentially inhibiting invasion. CHE also exhibited an inhibitory effect on the phosphorylation of PI3K, AKT, and mTOR, which is an upstream regulatory signaling pathway of MMP-2/9. In summary, CSCs derived from U2OS and MG-63 cells, CHE could inhibit the stemness and malignant behaviors of CSCs potentially by inhibiting the PI3K/AKT/mTOR signaling pathway.
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16
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Chrabańska M, Rynkiewicz M, Kiczmer P, Drozdzowska B. Immunohistochemical Expression of CD44, MMP-2, MMP-9, and Ki-67 as the Prognostic Markers in Non-Clear Cell Renal Cell Carcinomas-A Prospective Cohort Study. J Clin Med 2022; 11:jcm11175196. [PMID: 36079127 PMCID: PMC9457518 DOI: 10.3390/jcm11175196] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
CD44 is the most frequently reported marker of the cancer stem cells in renal cell carcinoma (RCC). Matrix metalloproteinases MMP-2 and MMP-9 are key regulators of tumor invasion and metastasis. The aim of this study was to investigate the clinicopathologic and prognostic values of the immunohistochemical expression of CD44, MMP2, MMP9, and Ki-67 in papillary and chromophobe RCCs. In the case of papillary RCC, MMP-2 expression was positively correlated with patient age (p < 0.05), while CD44 expression was positively correlated with tumor stage (τ = 0.26, p < 0.05). Moreover, CD44 expression positively correlated with MMP-9 (τ = 0.39, p < 0.05). In the case of chromophobe RCC, only Ki-67 expression was negatively correlated with tumor stage (τ = −0.44, p < 0.05). During follow-up, a death was documented in 6 patients with papillary RCC. In these patients, CD44 expression was not a significant factor affecting the overall survival of patients (p > 0.05), whereas there was a positive correlation between increased MMP-9 expression and shorter overall survival (p < 0.05). Taken together, carcinogenesis in papillary RCC is probably dependent on both cancer stem cells and metalloproteinases activity. Expression of CD44 and MMP-9 can significantly improve the prediction of papillary RCC prognosis in the future.
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17
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Sparić R, Andjić M, Babović I, Nejković L, Mitrović M, Štulić J, Pupovac M, Tinelli A. Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review. Int J Mol Sci 2022; 23:ijms23179728. [PMID: 36077127 PMCID: PMC9456512 DOI: 10.3390/ijms23179728] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 11/28/2022] Open
Abstract
Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990–2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.
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Affiliation(s)
- Radmila Sparić
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Koste Todorovića 26, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Mladen Andjić
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Koste Todorovića 26, 11000 Belgrade, Serbia
- Correspondence: (M.A.); (A.T.)
| | - Ivana Babović
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Koste Todorovića 26, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Lazar Nejković
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic of Gynecology and Obstetrics Narodni Front, 11000 Belgrade, Serbia
| | - Milena Mitrović
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Koste Todorovića 26, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Jelena Štulić
- Clinic of Gynecology and Obstetrics Narodni Front, 11000 Belgrade, Serbia
| | - Miljan Pupovac
- Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, Koste Todorovića 26, 11000 Belgrade, Serbia
| | - Andrea Tinelli
- Department of Obstetrics and Gynecology, and CERICSAL (CEntro di Ricerca Clinico SALentino), “Verisdelli Ponti Hospital”, Via Giuseppina Delli Ponti, 73020 Scorrano, LE, Italy
- Correspondence: (M.A.); (A.T.)
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18
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A Sulfated Polysaccharide from Red Algae ( Gelidium crinale) to Suppress Cells Metastasis and MMP-9 Expression of HT1080 Cells. Foods 2022; 11:foods11152360. [PMID: 35954126 PMCID: PMC9368188 DOI: 10.3390/foods11152360] [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: 06/14/2022] [Revised: 07/12/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
Sulfated polysaccharides from red algae have a variety of biological activities, especially antitumor activities. Matrix metalloproteinase-9 (MMP-9) is a proteolytic metalloenzyme that degrades the central part of the extracellular matrix (ECM) and promotes tumor metastasis. In this research, we have investigated the influence and mechanism of GNP (sulfated polysaccharide from Gelidium crinale) on tumor metastasis and MMP-9 expression of human fibrosarcoma (HT1080) cells. The results inflected that the concentration of GNP below 100 μg/mL has no toxicity to HT1080 cells, but showed excellent activity in inhibiting cells migration and invasion. In addition, GNP effectively inhibits the mRNA of MMP-9 and reduces its expression and activity by regulating nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPK) and mTOR/PI3K/Akt signaling pathways. GNP has great potential as MMP-9 inhibitor and could be developed as a functional food or drug to prevent tumor metastasis.
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19
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Hong OY, Jang HY, Lee YR, Jung SH, Youn HJ, Kim JS. Inhibition of cell invasion and migration by targeting matrix metalloproteinase-9 expression via sirtuin 6 silencing in human breast cancer cells. Sci Rep 2022; 12:12125. [PMID: 35840633 PMCID: PMC9287314 DOI: 10.1038/s41598-022-16405-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Sirtuin 6 (SIRT6) regulation is involved in carcinogenesis. However, its role in breast cancer (BC) metastasis remains unclear. We investigated the effects of SIRT6 on protein kinase C activator- and cytokine-mediated cancer cell invasion and migration in MCF-7 and MDA-MB-231 cells and the association between SIRT6 and matrix metalloproteinase-9 (MMP-9) expression. To assess MMP-9 and SIRT6 expression in patients, protein levels in BC tissues were analyzed. MCF-7 and MDA-MB-231 cell viability was analyzed using MTT assays. SIRT6 was silenced in both cell lines and protein secretion, expression, and mRNA levels were analyzed. Transcription factor DNA activity was investigated using luciferase assays. Matrigel invasion assays were used to assess the effects of SIRT6 in both cell lines. SIRT6 and MMP-9 expression in cancer tissues was significantly higher than in paired normal breast tissues. 12-O-tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) increased MMP-9 expression and cell invasion and migration, but SIRT6 knockdown abolished these effects. SIRT6 overexpression additively increased TPA- and TNF-α-induced MMP-9 expression. SIRT6 knockdown suppressed the mitogen-activated protein kinase (MAPK) signaling pathway and thus TPA- and TNF-α-induced MMP-9 expression. SIRT6 silencing suppressed TPA- and TNF-α-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) expressions in both cell lines, and treatment with MAPK, NF-κB, and AP-1 inhibitors reduced MMP-9 expression. The anti-invasive effects of SIRT6 in BC cells might be mediated by suppression of MAPK phosphorylation and reduction in NF-κB and AP-1 DNA activities, leading to MMP-9 downregulation, suggesting that SIRT6 modulation has the potential to target BC metastasis.
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Affiliation(s)
- On-Yu Hong
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea
| | - Hye-Yeon Jang
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea
| | - Young-Rae Lee
- Department of Oral Biochemistry, and Institute of Biomaterials, Implant, School of Dentistry, Wonkwang University, Iksan, Jeollabuk, 54538, Republic of Korea
| | - Sung Hoo Jung
- Department of Surgery, Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea
| | - Hyun Jo Youn
- Department of Surgery, Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea.
| | - Jong-Suk Kim
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin, Jeonju, Jeollabuk, 54907, Republic of Korea.
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20
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Munir MU. Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue. Cancers (Basel) 2022; 14:cancers14122904. [PMID: 35740570 PMCID: PMC9221319 DOI: 10.3390/cancers14122904] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 02/01/2023] Open
Abstract
Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review.
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Affiliation(s)
- Muhammad Usman Munir
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Aljouf, Saudi Arabia
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21
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Shafiee G, Saidijam M, Tayebinia H, Khodadadi I. Beneficial effects of genistein in suppression of proliferation, inhibition of metastasis, and induction of apoptosis in PC3 prostate cancer cells. Arch Physiol Biochem 2022; 128:694-702. [PMID: 31985311 DOI: 10.1080/13813455.2020.1717541] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Beneficial effects of genistein have been studied in various cancer types but the underlying molecular mechanisms of its actions have not been well established. This study investigated the effects of genistein on caspase-3 and p38 mitogen-activated protein kinase (p38MAPK) as main cellular signalling targets in PC3 prostate cancer cells. METHODS Caspase-3 and p38MAPK gene expression and intracellular protein levels were determined. Matrix metalloproteinase-2 (MMP2) gelatinase activity and caspase-3 enzyme activity were measured and PC3 cell migration and proliferation potencies were assessed. RESULTS Genistein induced apoptosis by enhancing the gene expression, intracellular protein level, and enzyme activity of caspase-3. Genistein also inhibited cell proliferation by reducing p38MAPK gene expression and protein level and strongly suppressed metastatic potency of PC3 cells by reducing MMP2 activity. CONCLUSION Genistein exhibits its beneficial anticancer properties on PC3 cells by reducing metastatic potency and regulating caspase-3 and p38MAPK pathways at different transcriptional and protein levels.
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Affiliation(s)
- Gholamreza Shafiee
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Department of Molecular Medicine and Human Genetics, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heidar Tayebinia
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Khodadadi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Nutrition Health Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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22
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Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome. iScience 2022; 25:104269. [PMID: 35542046 PMCID: PMC9079005 DOI: 10.1016/j.isci.2022.104269] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 03/12/2022] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Large offspring syndrome (LOS) and Beckwith-Wiedemann syndrome are similar epigenetic congenital overgrowth conditions in ruminants and humans, respectively. We have reported global loss-of-imprinting, methylome epimutations, and gene misregulation in LOS. However, less than 4% of gene misregulation can be explained with short range (<20kb) alterations in DNA methylation. Therefore, we hypothesized that methylome epimutations in LOS affect chromosome architecture which results in misregulation of genes located at distances >20kb in cis and in trans (other chromosomes). Our analyses focused on two imprinted domains that frequently reveal misregulation in these syndromes, namely KvDMR1 and IGF2R. Using bovine fetal fibroblasts, we identified CTCF binding at IGF2R imprinting control region but not KvDMR1, and allele-specific chromosome architecture of these domains in controls. In LOS, analyses identified erroneous long-range contacts and clustering tendency in the direction of expression of misregulated genes. In conclusion, altered chromosome architecture is associated with LOS.
IGF2R imprinted domain has allele-specific chromosome architecture in bovines In bovines, CTCF binds at IGF2R imprinting control region but not at KvDMR1 Bovine large offspring syndrome (LOS) shows altered chromosome architecture at IGF2R Misregulated genes in LOS exhibit genomic location-based clustering tendency
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23
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Pan Y, Fan Y, Lu Y, Peng S, Lin H, Deng Q. Molecular characterization of matrix metalloproteinase gene family across primates. Aging (Albany NY) 2022; 14:3425-3445. [PMID: 35444067 PMCID: PMC9085222 DOI: 10.18632/aging.204021] [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: 10/12/2021] [Accepted: 04/12/2022] [Indexed: 11/25/2022]
Abstract
Deregulation of matrix metalloproteinases (MMPs) contributes considerably to cancers, psychiatric disorders, macular degeneration and bone diseases. The use of humans in the development of MMPs as prognostic biomarkers and therapeutic targets is complicated by many factors, while primate models can be useful alternatives for this purpose. Here, we performed genome-enabled identification of putative MMPs across primate species, and comprehensively investigated the genes. Phylogenetic topology of the MMP family showed each type formulates a distinct clade, and was further clustered to classes, largely agreeing with classification based on biochemical properties and domain organization. Across primates, the excess of candidate sites of positive selection was detected for MMP-19, in addition to 1-3 sites in MMP-8, MMP-10 and MMP-26. MMP-26 showed Ka/Ks value above 1 between human and chimpanzee copies. We observed two copies of MMP-19 in the old-world monkey genomes, suggesting gene duplication at the early stage of or prior to the emergence of the lineage. Furin-activatable MMPs demonstrate the most variable properties regarding Domain organization and gene structure. During human aging, MMP-11 showed gradually decreased expression in testis, so as MMP-2, MMP-14, MMP15 and MMP-28 in ovary, while MMP-7 and MMP-21 showed elevated expression, implying their distinct roles in different reproductive organs. Co-expression clusters were formed among human MMPs both within and across classes, and expression correlation was observed in MMP genes across primates. Our results illuminate the utilization of MMPs for the discovery of prognostic biomarkers and therapeutic targets for aging-related diseases and carry new messages on MMP classification.
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Affiliation(s)
- Yinglian Pan
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan, People's Republic of China
| | - Yadan Fan
- Department of Gynecology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, People's Republic of China
| | - Yanda Lu
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan, People's Republic of China
| | - Siyuan Peng
- Department of Gynecology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, People's Republic of China
| | - Haixue Lin
- Department of Gynecology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, People's Republic of China
| | - Qingchun Deng
- Department of Gynecology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, People's Republic of China
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Mamie C, Bruckner RS, Lang S, Shpigel NY, Turina M, Rickenbacher A, Cabalzar-Wondberg D, Chvatchko Y, Rogler G, Scharl M. MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model. Tissue Barriers 2022; 10:1994350. [PMID: 34709129 PMCID: PMC9067458 DOI: 10.1080/21688370.2021.1994350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/07/2021] [Accepted: 10/10/2021] [Indexed: 10/20/2022] Open
Abstract
Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.
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Affiliation(s)
- Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ramona S. Bruckner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nahum Y. Shpigel
- Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Matthias Turina
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andreas Rickenbacher
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Daniela Cabalzar-Wondberg
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Hong OY, Kang SY, Noh EM, Yu HN, Jang HY, Kim SH, Hong J, Chung EY, Kim JS. Aurora kinase A induces migration and invasion by inducing epithelial-to-mesenchymal transition in colon cancer cells. BMB Rep 2022. [PMID: 34903321 PMCID: PMC8891622 DOI: 10.5483/bmbrep.2022.55.2.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- On-Yu Hong
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Sang Yull Kang
- Department of Surgery, Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
| | - Eun-Mi Noh
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Hong-Nu Yu
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Hye-Yeon Jang
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Seong-Hun Kim
- Division of Gastroenterology, Department of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea
| | - Jingyu Hong
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Eun Yong Chung
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jong-Suk Kim
- Department of Biochemistry, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
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Salidroside, 8( E)-Nuezhenide, and Ligustroside from Ligustrum japonicum Fructus Inhibit Expressions of MMP-2 and -9 in HT 1080 Fibrosarcoma. Int J Mol Sci 2022; 23:ijms23052660. [PMID: 35269801 PMCID: PMC8910403 DOI: 10.3390/ijms23052660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 12/19/2022] Open
Abstract
A phenyl ethanoid, salidroside (SAL), and two secoiridoids, 8(E)-nuezhenide (NZD) and ligustroside (LIG), were isolated from fruits of Ligustrumjaponicum, used as traditional folk medicine, and their chemical structures were elucidated by the comparison of spectral data with published literature. Matrix metalloproteinases (MMPs) are major enzymes that play crucial roles in the metastasis and invasive behavior of tumors. In particular, MMP-2 and MMP-9, regulated by the MAPK signaling pathways, including p38, ERK and JNK, are known to play a key role in the degradation of the basement membrane. In the present study, the effects of SAL, NZD and LIG on the expression of MMP-2 and -9 were examined in phorbol 12-myristate 13-acetate (PMA)-induced HT 1080 cells. All the compounds significantly lowered the amount of MMP-2 and MMP-9 released, as determined by gelatin zymography and ELISA. In addition, the mRNA and protein expression levels of MMP-2 and MMP-9 were significantly suppressed, as measured by RT-PCR and Western blotting. According to the Western blotting assay, SAL and LIG effectively reduced the expression of MMP-2 in a dose-dependent manner. NZD lowered the expression of MMP-9 in a similar way. The phosphorylation of p38, ERK and JNK was also significantly suppressed by these compounds. These findings suggest that all the compounds regulate the release and expression of MMP-2 and MMP-9 via MAPK signaling pathways.
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Baldini L, Lenci E, Bianchini F, Trabocchi A. Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis. Molecules 2022; 27:molecules27041249. [PMID: 35209039 PMCID: PMC8879803 DOI: 10.3390/molecules27041249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/10/2022] Open
Abstract
During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of αvβ3 and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and αvβ3, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and αvβ3 RGD integrin.
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Affiliation(s)
- Lorenzo Baldini
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy; (L.B.); (E.L.)
| | - Elena Lenci
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy; (L.B.); (E.L.)
| | - Francesca Bianchini
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy;
| | - Andrea Trabocchi
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy; (L.B.); (E.L.)
- Correspondence:
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Wang L, Chen H, Wang F, Zhang X. The development of peptide-drug conjugates (PDCs) strategies for paclitaxel. Expert Opin Drug Deliv 2022; 19:147-161. [PMID: 35130795 DOI: 10.1080/17425247.2022.2039621] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Paclitaxel is a powerful and effective anti-tumor drug with wide clinical application. However, there are still some limitations, including poor water solubility, low specificity, and susceptibility to drug resistance. The peptide-drug conjugates (PDCs) represent a rising class of therapeutic drugs, which combines small-molecule chemotherapeutic drugs with highly flexible peptides through a cleavable or non-cleavable linker. When this strategy is applied, the therapeutic effects of paclitaxel can be improved. AREAS COVERED In this review, we discuss the application of the PDCs strategy in paclitaxel, including two parts: the tumor targeting peptide-paclitaxel conjugates and the cell penetrating peptide-paclitaxel conjugates. EXPERT OPINION Combining drugs with multifunctional peptides covalently is an effective strategy for delivering paclitaxel to tumors. Depending on different functional peptides, conjugates can increase the water solubility of paclitaxel, tumor permeability of paclitaxel, the accumulation of paclitaxel in tumor tissues, and enhance the antitumor effect of paclitaxel. In addition, due to the change of cell entry mechanism, partial conjugates can restore the therapeutic activity of paclitaxel against resistant tumors. Notably, in order to better translate into the clinical field in the future, more research should be conducted to ensure the safety and effectiveness of peptide-paclitaxel conjugates.
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Affiliation(s)
- Longkun Wang
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, People's Republic of China
| | - Hongyuan Chen
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan 250012, People's Republic of China
| | - Fengshan Wang
- Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, People's Republic of China
| | - Xinke Zhang
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, People's Republic of China
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Moritz MNDO, Casali BC, Stotzer US, Karina dos Santos P, Selistre-de-Araujo HS. Alternagin-C, an alpha2beta1 integrin ligand, attenuates collagen-based adhesion, stimulating the metastasis suppressor 1 expression in triple-negative breast tumor cells. Toxicon 2022; 210:1-10. [DOI: 10.1016/j.toxicon.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/17/2022] [Accepted: 02/02/2022] [Indexed: 11/28/2022]
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Verhulst E, Garnier D, De Meester I, Bauvois B. Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go? Cancers (Basel) 2022; 14:624. [PMID: 35158891 PMCID: PMC8833564 DOI: 10.3390/cancers14030624] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.
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Affiliation(s)
- Emile Verhulst
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (E.V.); (I.D.M.)
| | - Delphine Garnier
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France;
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (E.V.); (I.D.M.)
| | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France;
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31
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Holm JB, Rosendahl AH, Borgquist S. Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer. Cancers (Basel) 2021; 13:cancers13246286. [PMID: 34944905 PMCID: PMC8699696 DOI: 10.3390/cancers13246286] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Breast cancer is the second most common cancer in women worldwide. The risk of developing breast cancer depends on various mechanisms, such as age, heredity, reproductive factors, physical inactivity, and obesity. Obesity increases the risk of breast cancer and worsens outcomes for breast cancer patients. The rate of obesity is increasing worldwide, stressing the need for awareness of the association between obesity and breast cancer. In this review, we outline the biomarkers—including cellular and soluble factors—in the breast, associated with obesity, that affect the risk of breast cancer and breast cancer prognosis. Through these biomarkers, we aim to better identify patients with obesity with a higher risk of breast cancer and an inferior prognosis. Abstract Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.
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Affiliation(s)
- Jonas Busk Holm
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Correspondence: (J.B.H.); (S.B.)
| | - Ann H. Rosendahl
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
| | - Signe Borgquist
- Department of Oncology, Aarhus University Hospital, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Department of Clinical Sciences Lund, Oncology, Lund University, Skåne University Hospital, Barngatan 4, 221 85 Lund, Sweden;
- Correspondence: (J.B.H.); (S.B.)
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Dai J, Dong X, Wang Q, Lou X, Xia F, Wang S. PEG-Polymer Encapsulated Aggregation-Induced Emission Nanoparticles for Tumor Theranostics. Adv Healthc Mater 2021; 10:e2101036. [PMID: 34414687 DOI: 10.1002/adhm.202101036] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/28/2021] [Indexed: 12/15/2022]
Abstract
In the field of tumor imaging and therapy, the aggregation-caused quenching (ACQ) effect of fluorescent dyes at high concentration is a great challenge. In this regard, the aggregation-induced emission luminogens (AIEgens) show great potential, since AIEgens effectively overcome the ACQ effect and have better fluorescence quantum yield, photobleaching resistance, and photosensitivity. Polyethylene glycol (PEG)-polymer is the most commonly used carrier to prepare nanoparticles (NPs). The advantage of PEGylation is that it can greatly prolong the metabolic half-life and reduce immunogenicity and toxicity. Considering that the hydrophobicity of most AIEgens hinders their application in organisms, the use of PEG-polymer encapsulation is an effective strategy to overcome this obstacle. Importantly, bioactive functional groups can be modified on PEG-polymers to enhance the biological effect of NPs. The combination of powerful AIEgens and PEG-polymers provides a new strategy for tumor imaging and therapy, which is promising for clinical application.
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Affiliation(s)
- Jun Dai
- Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan 430032 China
| | - Xiaoqi Dong
- State Key Laboratory of Biogeology and Environmental Geology Faculty of Materials Science and Chemistry China University of Geosciences 388 Lumo Road Wuhan 430074 China
| | - Quan Wang
- State Key Laboratory of Biogeology and Environmental Geology Faculty of Materials Science and Chemistry China University of Geosciences 388 Lumo Road Wuhan 430074 China
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology Faculty of Materials Science and Chemistry China University of Geosciences 388 Lumo Road Wuhan 430074 China
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology Faculty of Materials Science and Chemistry China University of Geosciences 388 Lumo Road Wuhan 430074 China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan 430032 China
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N-myc Downstream-Regulated Gene 2 (NDRG2) Function as a Positive Regulator of Apoptosis: A New Insight into NDRG2 as a Tumor Suppressor. Cells 2021; 10:cells10102649. [PMID: 34685629 PMCID: PMC8534062 DOI: 10.3390/cells10102649] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/12/2022] Open
Abstract
N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that increases tumor sensitivity to anticancer drugs, slows tumor progression, and inhibits metastasis. NDRG2 is suppressed in various aggressive tumor positions, whereas NDRG2 expression is associated with patient prognosis, such as an improved survival rate. In this review, we summarize the tumor suppressor mechanism of NDRG2 and provide information on the function of NDRG2 concerning the susceptibility of cells to apoptosis. NDRG2 increases the susceptibility to apoptosis in various physiological environments of cells, such as development, hypoxia, nutrient deprivation, and cancer drug treatment. Although the molecular and cell biological mechanisms of NDRG2 have not been fully elucidated, we provide information on the mechanisms of NDRG2 in relation to apoptosis in various environments. This review can assist the design of research regarding NDRG2 function and suggests the potential of NDRG2 as a molecular target for cancer patients.
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Takahashi M, Umehara Y, Yue H, Trujillo-Paez JV, Peng G, Nguyen HLT, Ikutama R, Okumura K, Ogawa H, Ikeda S, Niyonsaba F. The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway. Front Immunol 2021; 12:712781. [PMID: 34594328 PMCID: PMC8476922 DOI: 10.3389/fimmu.2021.712781] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/27/2021] [Indexed: 01/15/2023] Open
Abstract
In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.
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Affiliation(s)
- Miho Takahashi
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshie Umehara
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hainan Yue
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Ge Peng
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hai Le Thanh Nguyen
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Risa Ikutama
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ko Okumura
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideoki Ogawa
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigaku Ikeda
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - François Niyonsaba
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan
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Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy. Biochem J 2021; 478:1139-1157. [PMID: 33600567 PMCID: PMC7959692 DOI: 10.1042/bcj20200628] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 02/09/2021] [Accepted: 02/17/2021] [Indexed: 12/11/2022]
Abstract
Crosstalk of the oncogenic matrix metalloproteinase-9 (MMP9) and one of its ligands, CD44, involves cleavage of CD44 by the MMP9 catalytic domain, with the CD44–MMP9 interaction on the cell surface taking place through the MMP9 hemopexin domain (PEX). This interaction promotes cancer cell migration and invasiveness. In concert, MMP9-processed CD44 induces the expression of MMP9, which degrades ECM components and facilitates growth factor release and activation, cancer cell invasiveness, and metastasis. Since both MMP9 and CD44 contribute to cancer progression, we have developed a new strategy to fully block this neoplastic process by engineering a multi-specific inhibitor that simultaneously targets CD44 and both the catalytic and PEX domains of MMP9. Using a yeast surface display technology, we first obtained a high-affinity inhibitor for the MMP9 catalytic domain, which we termed C9, by modifying a natural non-specific MMP inhibitor, N-TIMP2. We then conjugated C9 via a flexible linker to PEX, thereby creating a multi-specific inhibitor (C9-PEX) that simultaneously targets the MMP9 catalytic and PEX domains and CD44. It is likely that, via its co-localization with CD44, C9-PEX may compete with MMP9 localization on the cell surface, thereby inhibiting MMP9 catalytic activity, reducing MMP9 cellular levels, interfering with MMP9 homodimerization, and reducing the activation of downstream MAPK/ERK pathway signaling. The developed platform could be extended to other oncogenic MMPs as well as to other important target proteins, thereby offering great promise for creating novel multi-specific therapeutics for cancer and other diseases.
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In silico modeling and molecular docking insights of kaempferitrin for colon cancer-related molecular targets. JOURNAL OF SAUDI CHEMICAL SOCIETY 2021. [DOI: 10.1016/j.jscs.2021.101319] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Ghadaksaz A, Imani Fooladi AA, Mahmoodzadeh Hosseini H, Nejad Satari T, Amin M. ARA-linker-TGFαL3: a novel chimera protein to target breast cancer cells. Med Oncol 2021; 38:96. [PMID: 34273028 DOI: 10.1007/s12032-021-01546-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/05/2021] [Indexed: 10/20/2022]
Abstract
Targeted cancer therapies based on overexpressed receptors and the fractions containing immunotoxins and bacterial metabolites are one of the well-known methods to overcome the chemotherapy resistance of cancer cells. In this paper, we designed ARA-linker-TGFαL3, using Arazyme, a Serratia proteamaculans metabolite, and a third loop segment of TGFα to target EGFR-expressing breast cancer cells. After cloning in pET28a (+), the expression of recombinant protein was optimized in Escherichia coli strain BL21 (DE3). MDA-MB-468 (EGFR positive) and MDA-MB-453 (EGFR negative) breast cancer cell lines were employed. Also, the chemotherapeutic drug, Taxotere (Docetaxel), was employed to compare cytotoxicity effects. Cell ELISA assessed the binding affinity of recombinant proteins to the receptor, and the cytotoxicity was detected by MTT and lactate dehydrogenase release assays. The interfacing with cancer cell adhesion was evaluated. Furthermore, the induction of apoptosis was examined utilizing flow cytometric analysis, and caspase-3 activity assay. Moreover, RT-PCR was conducted to study the expression of apoptosis (bax, bcl2, and casp3), angiogenesis (vegfr2), and metastasis (mmp2 and mmp9) genes. ARA-linker-TGFαL3 revealed a higher binding affinity, cytotoxicity, and early apoptosis induction in MDA-MB-468 cells compared to the effects of Arazyme while both recombinant proteins showed similar effects on MDA-MB-453. In addition, the Taxotere caused the highest cytotoxicity on cancer cells through induction of late apoptosis. Meanwhile, the expression of angiogenesis and metastasis genes was decreased in both cell lines after treatment with either ARA-linker-TGFαL3 or Arazyme. Our in vitro results indicated the therapeutic effect of ARA-linker-TGFαL3 on breast cancer cells.
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Affiliation(s)
- Abdolamir Ghadaksaz
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Hamideh Mahmoodzadeh Hosseini
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Taher Nejad Satari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohsen Amin
- Department of Drug and Food Control, Faculty of Pharmacy, and The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
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Lindhout IA, Murray TE, Richards CM, Klegeris A. Potential neurotoxic activity of diverse molecules released by microglia. Neurochem Int 2021; 148:105117. [PMID: 34186114 DOI: 10.1016/j.neuint.2021.105117] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/18/2021] [Accepted: 06/24/2021] [Indexed: 01/02/2023]
Abstract
Microglia are the professional immune cells of the brain, which support numerous physiological processes. One of the defensive functions provided by microglia involves secretion of cytotoxins aimed at destroying invading pathogens. It is also recognized that the adverse activation of microglia in diseased brains may lead to secretion of cytotoxic molecules, which could be damaging to the surrounding cells, including neurons. Several of these toxins, such as reactive oxygen and nitrogen species, L-glutamate, and quinolinic acid, are widely recognized and well-studied. This review is focused on a structurally diverse group of less-established microglia neurotoxins, which were selected by applying the two criteria that these molecules 1) can be released by microglia, and 2) have the potential to be directly harmful to neurons. The following 11 molecules are discussed in detail: amyloid beta peptides (Aβ); cathepsin (Cat)B and CatD; C-X-C motif chemokine ligand (CXCL)10 and CXCL12 (5-67); high mobility group box (HMGB)1; lymphotoxin (LT)-α; matrix metalloproteinase (MMP)-2 and MMP-9; platelet-activating factor (PAF); and prolyl endopeptidase (PEP). Molecular mechanisms of their release by microglia and neurotoxicity, as well as available evidence implicating their involvement in human neuropathologies are summarized. Further studies on several of the above molecules are warranted to confirm either their microglial origin in the brain or direct neurotoxic effects. In addition, investigations into the differential secretion patterns of neurotoxins by microglia in response to diverse stimuli are required. This research could identify novel therapeutic targets for neurological disorders involving adverse microglial activation.
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Affiliation(s)
- Ivan A Lindhout
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Taryn E Murray
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Christy M Richards
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada.
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Elekofehinti OO, Iwaloye O, Olawale F, Ariyo EO. Saponins in Cancer Treatment: Current Progress and Future Prospects. PATHOPHYSIOLOGY 2021; 28:250-272. [PMID: 35366261 PMCID: PMC8830467 DOI: 10.3390/pathophysiology28020017] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022] Open
Abstract
Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.
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Affiliation(s)
- Olusola Olalekan Elekofehinti
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
| | - Opeyemi Iwaloye
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
| | - Femi Olawale
- Nanogene and Drug Delivery Group, Department of Biochemistry, University of Kwa-Zulu Natal, Durban 4000, South Africa;
- Department of Biochemistry, College of Medicine, University of Lagos, Lagos 101017, Nigeria
| | - Esther Opeyemi Ariyo
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
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Tiribelli M, Michelutti A, Cavallin M, Di Giusto S, Fanin R, Damiani D. Impact of Concomitant Aberrant CD200 and BCL2 Overexpression on Outcome of Acute Myeloid Leukemia: A Cohort Study from a Single Center. Turk J Haematol 2021; 38:119-125. [PMID: 33596632 PMCID: PMC8171206 DOI: 10.4274/tjh.galenos.2021.2020.0728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective: CD200 and BCL2 overexpression is independently associated with inferior survival in acute myeloid leukemia (AML), and these two factors are frequently co-expressed; however, no data are available on the role of concomitant aberrant CD200 and BCL2 expression on outcome of AML patients. We aimed to elucidate the prognostic role of CD200/BCL2 co-expression and its association with specific leukemia subsets. Materials and Methods: We analyzed 242 adult AML patients uniformly treated with intensive chemotherapy, evaluating the impact of CD200 and BCL2 expression on complete remission (CR), disease-free survival, and overall survival (OS). Results: CD200 and BCL2 were expressed in 139 (57.4%) and 137 (56.6%) cases, respectively, with 92 patients (38%) displaying double positivity (DP), 58 (24%) displaying double negativity (DN), and 92 patients expressing only either CD200 (n=47) or BCL2 (n=45). CR was achieved in 71% of cases, being less frequent in DP patients (60%) compared to other groups (76%-81%, p<0.001). In the whole population 3-year OS was 44%, being lower in DP patients (28%) than in patients with single CD200 or BCL2 expression (47%) or DN cases (60%; p=0.004). Other factors associated with worse OS were advanced age, CD34 positivity, secondary AML, and high white blood cell count at diagnosis; combining these 4 factors with CD200/BCL2 DP, we identified 6 groups with significantly different rates of survival (3-year OS ranging from 90% to 0%). Conclusion: Our data support a synergistic effect of CD200 and BCL2 in AML cells, conferring an enhanced survival capacity in a permissive microenvironment and resulting in worse prognosis.
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Affiliation(s)
- Mario Tiribelli
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
| | - Angela Michelutti
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
| | - Margherita Cavallin
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
| | - Sara Di Giusto
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
| | - Renato Fanin
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
| | - Daniela Damiani
- University of Udine, Department of Medical Area, Division of Hematology and Stem Cell Transplantation, Udine, Italy
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Cancer-Associated Fibroblasts Regulate Bladder Cancer Invasion and Metabolic Phenotypes through Autophagy. DISEASE MARKERS 2021; 2021:6645220. [PMID: 34122670 PMCID: PMC8169272 DOI: 10.1155/2021/6645220] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/18/2021] [Accepted: 05/15/2021] [Indexed: 12/19/2022]
Abstract
Recently, both cancer-associated fibroblasts (CAFs) and autophagy have been proven to play an important role in tumor development, including bladder cancer (BCa). However, the real mechanisms remain largely unclear. Here, we reconstruct a mimic tumor microenvironment to explore the interaction between CAFs and the BCa cell line T24 using a coculture system. Autophagy in CAFs was induced or inhibited by rapamycin or siRNA, respectively. After coculture with CAFs, T24 cell proliferation, invasion, and aerobic glycolysis were tested in vitro. Rapamycin induced and siAtg5 inhibited autophagy in CAFs. Enhanced autophagy in CAFs promoted cell proliferation and invasion in T24 cells in vitro, while there was no significant difference between the autophagy-inhibited group and the controls. Lactate concentration was elevated in both rapamycin-treated and siAtg5-treated groups compared with the control group. In addition, the expression levels of MCT1, MCT4, HK2, SLC2A1, and MMP-9 were all increased in T24 cells in the autophagy-enhanced group. Our results indicated that CAFs could regulate BCa invasion and metabolic phenotypes through autophagy, providing us with new alternative treatments for BCa in the future.
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Romano R, Calcagnile M, Margiotta A, Franci L, Chiariello M, Alifano P, Bucci C. RAB7A Regulates Vimentin Phosphorylation through AKT and PAK. Cancers (Basel) 2021; 13:cancers13092220. [PMID: 34066419 PMCID: PMC8125308 DOI: 10.3390/cancers13092220] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary RAB7A (RAs-related in Brain 7A) is a master regulator of intracellular traffic controlling transport to late endosomes and lysosomes, two organelles of the endocytic pathway important for degradation. Thanks to this function, RAB7A is also involved in cellular processes linked to cancer, such as apoptosis, cytoskeletal reorganization, and cell migration. Therefore, the interest in the role of RAB7A in cancer progression is increasing. Previously, we demonstrated that RAB7A regulates phosphorylation and assembly of vimentin, a cytoskeletal intermediate filament protein, which is also an important mesenchymal marker of cancer cells. The aim of the present study is the identification of the kinases responsible for vimentin phosphorylation whose activity is affected by the modulation of RAB7A expression. We found that RAB7A is able to regulate AKT (also called protein kinase B or PKB) and PAK1 (P21-Activated Kinase 1) and several of their downstream effectors, which control proliferation, apoptosis, survival, migration, and invasion. These data suggest that RAB7A could have a key role in cancer development. Abstract RAB7A is a small GTPase that controls the late endocytic pathway but also cell migration through RAC1 (Ras-related C3 botulinum toxin substrate 1) and vimentin. In fact, RAB7A regulates vimentin phosphorylation at different sites and vimentin assembly, and, in this study, we identified vimentin domains interacting with RAB7A. As several kinases could be responsible for vimentin phosphorylation, we investigated whether modulation of RAB7A expression affects the activity of these kinases. We discovered that RAB7A regulates AKT and PAK1, and we demonstrated that increased vimentin phosphorylation at Ser38 (Serine 38), observed upon RAB7A overexpression, is due to AKT activity. As AKT and PAK1 are key regulators of several cellular events, we investigated if RAB7A could have a role in these processes by modulating AKT and PAK1 activity. We found that RAB7A protein levels affected beta-catenin and caspase 9 expression. We also observed the downregulation of cofilin-1 and decreased matrix metalloproteinase 2 (MMP2) activity upon RAB7A silencing. Altogether these results demonstrate that RAB7A regulates AKT and PAK1 kinases, affecting their downstream effectors and the processes they regulate, suggesting that RAB7A could have a role in a number of cancer hallmarks.
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Affiliation(s)
- Roberta Romano
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (R.R.); (M.C.); (A.M.); (P.A.)
| | - Matteo Calcagnile
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (R.R.); (M.C.); (A.M.); (P.A.)
| | - Azzurra Margiotta
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (R.R.); (M.C.); (A.M.); (P.A.)
| | - Lorenzo Franci
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), 53100 Siena, Italy; (L.F.); (M.C.)
- Core Research Laboratory (CRL), Istituto per lo Studio, La Prevenzione e la Rete Oncologica (ISPRO), 53100 Siena, Italy
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Mario Chiariello
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), 53100 Siena, Italy; (L.F.); (M.C.)
- Core Research Laboratory (CRL), Istituto per lo Studio, La Prevenzione e la Rete Oncologica (ISPRO), 53100 Siena, Italy
| | - Pietro Alifano
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (R.R.); (M.C.); (A.M.); (P.A.)
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (R.R.); (M.C.); (A.M.); (P.A.)
- Correspondence: ; Tel.: +39-0832-298900
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Charris KE, Rodrigues JR, Ramírez H, Fernandez-Moreira E, Ángel JE, Charris JE. Synthesis of 5H-indeno[1,2-b]pyridine derivatives: Antiproliferative and antimetastatic activities against two human prostate cancer cell lines. Arch Pharm (Weinheim) 2021; 354:e2100092. [PMID: 33928662 DOI: 10.1002/ardp.202100092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/04/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022]
Abstract
This study describes the direct synthesis of 2-amino-4-(phenylsubstituted)-5H-indeno[1,2-b]pyridine-3-carbonitrile derivatives 5-21, through sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-indanone in the presence of ammonium acetate and acetic acid (catalytic). The biological study showed that compound 10 significantly impeded proliferation of the cell lines PC-3, LNCaP, and MatLyLu. The antimetastatic effects of compound 10 could be related with inhibition of MMP9 in the PC-3 and LNCaP human cell lines. On the basis of a study of the structure-activity relationship of these compounds, we propose that the presence of two methoxy groups at positions 6 and 7 of the indeno nucleus and a 4-hydroxy-3-methoxy phenyl substitution pattern at position 4 of the pyridine ring is decisive for these types of molecules to exert very good antiproliferative and antimetastatic activities.
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Affiliation(s)
- Katiuska E Charris
- Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Caracas, Venezuela
| | - Juan R Rodrigues
- Departamento de Tecnología de Procesos Biológicos y Bioquímicos, División de Ciencias Biológicas, Universidad Simón Bolívar, Caracas, Venezuela
| | - Hegira Ramírez
- Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Caracas, Venezuela.,Facultad de Medicina, Universidad de Las Américas, Quito, Ecuador
| | | | - Jorge E Ángel
- Organic Synthesis Laboratory, Design and Pharmacological Evaluation of New Products, Experimental Faculty of Science, Central University of Venezuela, Zulia University, Maracaibo, Venezuela
| | - Jaime E Charris
- Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Caracas, Venezuela
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Bhatia M, Bhalerao M, Cruz-Martins N, Kumar D. Curcumin and cancer biology: Focusing regulatory effects in different signalling pathways. Phytother Res 2021; 35:4913-4929. [PMID: 33837579 DOI: 10.1002/ptr.7121] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/20/2021] [Accepted: 03/26/2021] [Indexed: 12/20/2022]
Abstract
Cancer is the second-leading cause of death worldwide. Till date, many such effective treatments are available, for example chemotherapy, surgery, and radiation therapy, but there are severe associated side effects, such as increased infection risk, constipation, hair loss, anaemia, among others. Thus, the need for effective therapeutic strategies and screening methodology arises. Researchers around the world are increasingly trying to discover anticancer therapies with as few side effects as possible and many are now focusing on phytochemicals, like curcumin. Curcumin is a bright yellow substance isolated from the plant rhizomes of Curcuma longa L. To this molecule a high therapeutic benefit has been underlined, being able to alter the development of cancer by different mechanisms, such as regulating multiple microRNA expression, modifying a series of signalling pathways, that is, Akt, Bcl-2, PTEN, p53, Notch, and Erbb. Another major pathway that curcumin targets is the matrix metalloproteinase (MMP) gene expression. In fact, MMPs are responsible for the degradation of the cell-extracellular matrix, which can lead to the diseased condition and many different pathways contribute to its activity, such as JAK/STAT, NF-κB, MAPK/ERK, COX-2, ROS, TGF-β, among others. In this review, we have attempted to describe the curcumin regulatory effect on different cell signalling pathways involved in the progression of different types of cancers.
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Affiliation(s)
- Muskan Bhatia
- Poona college of pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Mihir Bhalerao
- Poona college of pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.,Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
| | - Dileep Kumar
- Poona college of pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, India
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From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside. Int J Mol Sci 2021; 22:ijms22052697. [PMID: 33800057 PMCID: PMC7962130 DOI: 10.3390/ijms22052697] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 12/22/2022] Open
Abstract
Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.
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Wątroba S, Wiśniowski T, Bryda J, Kurzepa J. Characteristics of matrix metalloproteinases and their role in embryogenesis of the mammalian respiratory system. POSTEP HIG MED DOSW 2021. [DOI: 10.5604/01.3001.0014.6933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Summary
The human respiratory system appears as an outgrowth from the ventral wall of the primary foregut and its development includes a series of subsequent processes, dependent on the interactions between endothelial cells, respiratory epithelium and extracellular matrix (ECM). These interactions determine the acquisition of normal structural and functional features of the newly created tissues. The essential role in the morphogenesis of the respiratory system is performed by matrix metalloproteinases (MMPs). MMPs are endopeptidases containing zinc ion in their active center, necessary for the processes of hydrolysis of peptide bonds of substrates. The production of MMPs takes place in most connective tissue cells, leukocytes, macrophages, vascular endothelial cells as well as in neurons, glial cells and in tumor cells. Like other proteolytic enzymes, MMPs are produced and secreted in the form of inactive pro-enzymes, and their activation occurs in the extracellular space. MMPs perform both physiological and pathological functions during tissue modeling and their role in embryogenesis is based on the regulation of angiogenesis processes, stroma formation and cells migration. This article aims to characterize, discuss and demonstrate the activity and the role of MMPs in the subsequent stages of respiratory development.
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Affiliation(s)
- Sławomir Wątroba
- Department of Neonatology and Neonatal Intensive Care Unit , Independent Public Healthcare , Puławy , Poland
| | - Tomasz Wiśniowski
- Department of Urology and Urological Oncology , St. John of God Independent Public Provincial Hospital , Lublin , Poland
| | - Jarosław Bryda
- Department of Veterinary Hygiene , Voivodship Veterinary Inspectorate , Lublin , Poland
| | - Jacek Kurzepa
- Department of Medical Chemistry , Medical University , Lublin , Poland
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Do HTT, Cho J. Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells. Int J Mol Sci 2020; 22:ijms22010089. [PMID: 33374849 PMCID: PMC7796296 DOI: 10.3390/ijms22010089] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.
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Byun JH, Choi CW, Jang MJ, Lim SH, Han HJ, Choung SY. Anti-Osteoarthritic Mechanisms of Chrysanthemum zawadskii var. latilobum in MIA-Induced Osteoarthritic Rats and Interleukin-1β-Induced SW1353 Human Chondrocytes. ACTA ACUST UNITED AC 2020; 56:medicina56120685. [PMID: 33321982 PMCID: PMC7762971 DOI: 10.3390/medicina56120685] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022]
Abstract
Background and objectives: Chrysanthemum zawadskii var. latilobum (CZ), which has traditionally been used as a oriental tea in Asia, is known to have anti-inflammatory effects in osteoarthritis (OA). But the mechanism of these effects has not been made clear and it needs to be elucidated specifically for the clinical use of CZE in OA. Materials and Methods: To reveal this mechanism, we first identified which biomarkers were expressed in the joints of rats in which OA had been induced with monosodium iodoacetate and determined whether CZ extract (CZE) could normalize these biomarkers in the progression of OA. The anti-osteoarthritis effect of CZE was evaluated for its capability to inhibit levels of extracellular matrix (ECM)-degrading enzymes and enhance ECM synthesis. We also sought to identify whether the marker compound of CZE, linarin, has anti-osteoarthritic effects in the human chondrosarcoma cell line SW1353. Results: The changes in matrix metalloproteinases (MMPs) were remarkable: among them, MMP-1, MMP-3, MMP-9 and MMP-13 were most strongly induced, whereas their expressions were inhibited by CZE dose dependently. The expressions of the ECM synthetic genes, COL2A1 and ACAN, and the transcription factor SOX9 of these genes were reduced by OA induction and significantly normalized by CZE dose dependently. SOX9 is also a repressor of ECM-degrading aggrecanases, ADAMTS-4 and ADAMTS-5, and CZE significantly reduced the levels of these enzymes dose dependently. Similar results were obtained using the human chondrosarcoma cell line SW1353 with linarin, the biologically active compound of CZE. Conclusions: These anti-osteoarthritic effects suggest that CZE has mechanisms for activating ECM synthesis with SOX9 as well as inhibiting articular ECM-degrading enzymes.
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Affiliation(s)
- Jae-Hyuk Byun
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02453, Korea;
| | - Chi-Won Choi
- Department of Preventive Pharmacy and Toxicology, College of Pharmacy, Kyung Hee University, Seoul 02453, Korea;
| | - Min-Jung Jang
- Department of Research, GREEN CROSS Wellbeing Co., Ltd., Seongnam 13595, Korea; (M.-J.J.); (S.H.L.); (H.J.H.)
| | - Su Hwan Lim
- Department of Research, GREEN CROSS Wellbeing Co., Ltd., Seongnam 13595, Korea; (M.-J.J.); (S.H.L.); (H.J.H.)
| | - Hae Jung Han
- Department of Research, GREEN CROSS Wellbeing Co., Ltd., Seongnam 13595, Korea; (M.-J.J.); (S.H.L.); (H.J.H.)
| | - Se-Young Choung
- Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02453, Korea;
- Department of Preventive Pharmacy and Toxicology, College of Pharmacy, Kyung Hee University, Seoul 02453, Korea;
- Correspondence: ; Tel.: +82-29-6103-72
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Xie X, He H, Zhang N, Wang X, Rui W, Xu D, Zhu Y. Overexpression of DDR1 Promotes Migration, Invasion, Though EMT-Related Molecule Expression and COL4A1/DDR1/MMP-2 Signaling Axis. Technol Cancer Res Treat 2020; 19:1533033820973277. [PMID: 33234027 PMCID: PMC7705183 DOI: 10.1177/1533033820973277] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose: Discoidin domain receptor 1 (DDR1) belongs to a novel class of receptor tyrosine kinases. Previous evidence indicates that DDR1 overexpression promotes the aggressive growth of bladder cancer (BC) cells. This study aimed to investigate the molecular mechanisms by which DDR1 influences BC. Methods: DDR1 was transfected into human BC RT4 cells. DDR1, COL4A1, and MMP-2 expression in 30 BC tissues and paired adjacent tissues were examined by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Transwell assays were conducted to determine cell migration and invasion. RT-PCR and western blot (WB) were also used to measure the DDR1, COL4A1, MMP-2, and EMT-related gene (ZEB1 and SLUG) expression in RT4 cells after DDR1 overexpression. Results: COL4A1 and MMP-2 interacted with DDR1 in the PPI network. RT-PCR and immunohistochemistry results showed that both mRNA and protein levels of DDR1 and COL4A1 were significantly increased in BC tissue, while the expression of MMP-2 was increased only at the mRNA level (P < 0.05). Overexpression of DDR1 in RT4 cells significantly promoted their migratory and invasive capabilities in vitro (P < 0.05). Moreover, overexpression of DDR1 in RT4 cells increased the mRNA and protein expression of ZEB1, SLUG, COL4A1, and MMP-2 (P < 0.01). DDR1-mediated migration and invasion of RT4 cells were reversed after COL4A1-siRNA treatment. Conclusion: DDR1 may be a potential therapeutic target in BC patients.
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Affiliation(s)
- Xin Xie
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongchao He
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ning Zhang
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaojing Wang
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenbin Rui
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Danfeng Xu
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu Zhu
- Department of Urology, Ruijin Hospital, 56694Shanghai Jiaotong University School of Medicine, Shanghai, China
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50
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Zhang X, Zhai T, Hei Z, Zhou D, Jin L, Han C, Wang J. Effects of Platycodin D on apoptosis, migration, invasion and cell cycle arrest of gallbladder cancer cells. Oncol Lett 2020; 20:311. [PMID: 33093920 PMCID: PMC7573877 DOI: 10.3892/ol.2020.12174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 07/15/2020] [Indexed: 01/17/2023] Open
Abstract
Platycodin D (PD) is a triterpenoid saponin that exists in the roots of Platycodonis. It exhibits evident growth inhibitory effects and potent cytotoxicity against multiple types of cancer. Gallbladder cancer (GBC) is the most common malignant disease of the biliary tract system. Patients with GBC usually have limited available treatment strategies and a poor prognosis. The present study investigated the antitumor effects of PD on human GBC cells in vitro and its underlying molecular mechanisms of action. The results indicated that PD, as assessed using MTT and colony forming assays, induced evident growth inhibition. Flow cytometry indicated that PD robustly induced apoptosis and blocked GBC cells at the G2/M phase. Cell migration and invasion assays demonstrated that PD effectively inhibited the migratory and invasive abilities of GBC cell lines. Western blotting indicated that PD may initiate mitochondrial destruction in GBC cells through the JNK signaling pathway, thereby inducing apoptosis. The present results indicated that PD may exhibit antitumor effects by inducing apoptosis; inhibiting migration and invasion; and affecting the cell cycle in GBC cells. Therefore, PD has the potential to become a novel antitumor drug for GBC therapy.
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Affiliation(s)
- Xiaoyu Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Tianyu Zhai
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.,Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong university School of Medicine, Shanghai 200092, P.R. China
| | - Zhenyu Hei
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Di Zhou
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Longyang Jin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Chao Han
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Jiandong Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
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