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Altiparmak-Ulbegi G, Hasbal-Celikok G, Aksoy-Sagirli P. AKT1 and CTNNB1 mutations as drivers of paclitaxel resistance in breast cancer cells. Oncol Lett 2025; 30:324. [PMID: 40370645 PMCID: PMC12076040 DOI: 10.3892/ol.2025.15070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/26/2025] [Indexed: 05/16/2025] Open
Abstract
Breast cancer (BC) is the most prevalent cancer type in the world, with increasing incidence rates. Drug resistance is a notable factor that limits the effectiveness of BC therapy. Paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane class, is commonly used in BC; however, its efficacy is often compromised by drug resistance, which is primarily attributed to genetic alterations. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and wingless-type MMTV integration site family/β-catenin signaling pathways are involved in essential cellular processes, such as proliferation, apoptosis and maintenance of homeostasis. Dysregulated activation of these pathways is strongly associated with carcinogenesis and drug resistance. In the present study, the potential effects of AKT1 (E17K/E49K/L52R) and catenin β-1 (CTNNB1; S33P/T41A/S45F) mutations on PTX resistance in BC were investigated in vitro using site-directed mutagenesis, transient transfection, MTS assay and western blot analyses. The results of the present study indicated that AKT1-E17K/E49K and CTNNB1-S45F/T41A mutations induced PTX resistance compared with AKT1-wild-type (WT) and CTNNB1-WT in MCF-7 cells, respectively. In MDA-MB-231 cells, all three AKT1 mutations (E17K/E49K/L52R) triggered PTX resistance compared with AKT1-WT, while none of the CTNNB1 mutations exhibited such an effect. In conclusion, AKT1 mutations may serve as a biomarker for PTX resistance in both estrogen receptor (ER)(+)/progesterone receptor (PR)(+)/HER2(-) and triple negative BC, while CTNNB1 mutations may be a potential biomarker for PTX resistance in ER(+)/PR(+)/HER2(-) BC.
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Affiliation(s)
| | - Gozde Hasbal-Celikok
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
| | - Pinar Aksoy-Sagirli
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
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Ryspayeva D, Seyhan AA, MacDonald WJ, Purcell C, Roady TJ, Ghandali M, Verovkina N, El-Deiry WS, Taylor MS, Graff SL. Signaling pathway dysregulation in breast cancer. Oncotarget 2025; 16:168-201. [PMID: 40080721 PMCID: PMC11906143 DOI: 10.18632/oncotarget.28701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.
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Affiliation(s)
- Dinara Ryspayeva
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - William J. MacDonald
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Connor Purcell
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Tyler J. Roady
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - Maryam Ghandali
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Nataliia Verovkina
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
| | - Martin S. Taylor
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Brown Center on the Biology of Aging, Brown University, RI 02903, USA
| | - Stephanie L. Graff
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
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Wang Y, Liu W, Lai X, Miao H, Xiong X. PGAM1: a potential therapeutic target mediating Wnt/β-catenin signaling drives breast cancer progression. Discov Oncol 2025; 16:161. [PMID: 39934550 DOI: 10.1007/s12672-025-01939-z] [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: 09/10/2024] [Accepted: 02/05/2025] [Indexed: 02/13/2025] Open
Abstract
Phosphoglycerate mutase 1 (PGAM1) has been identified as a key player in the progression and metastasis of various human cancer types, including breast cancer (BC); however, its precise oncogenic mechanism remains unclear. The present study aimed to investigate the oncogenic mechanisms of PGAM1 and establish its potential as a therapeutic target. Comprehensive analyses from the Tumor Immune Estimation Resource 2.0 and The Cancer Genome Atlas databases revealed a significant upregulation of PGAM1 in BC, correlating with poor clinical outcomes. Additionally, elevated expression of PGAM1 was confirmed in clinical BC samples. Silencing PGAM1 with specific small hairpin RNA in BC cells resulted in a marked reduction in cell proliferation, invasiveness and migration, alongside increased apoptosis and cell cycle arrest. In vivo experiments using tumor-bearing nude mice demonstrated that PGAM1 knockdown significantly reduced tumor volume and weight, effectively inhibiting tumor growth. Mechanistic investigations suggested that PGAM1 promoted BC tumorigenesis through the activation of the Wnt/β-catenin signaling pathway, both in vitro and in vivo. Therefore, the upregulation of PGAM1 in BC enhances malignancy via the Wnt/β-catenin signaling pathway, highlighting PGAM1 as a promising therapeutic target for BC treatment.
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Affiliation(s)
- Yongxuan Wang
- Department of Pathology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Wei Liu
- Department of Breast Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Xudong Lai
- Department of Infectious Disease, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, Guangdong, China
| | - Haixiong Miao
- Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, 396 Tongfu Zhong Road, Guangzhou, 510220, Guangdong, China.
| | - Xifeng Xiong
- Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, 396 Tongfu Zhong Road, Guangzhou, 510220, Guangdong, China.
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Jiang L, Wang J, Liu Z, Zhang Q, Yang XL. Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis. FASEB J 2025; 39:e70294. [PMID: 39760229 PMCID: PMC11817322 DOI: 10.1096/fj.202401720r] [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: 07/26/2024] [Revised: 12/06/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025]
Abstract
Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared with matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes not only primary tumor growth but also establishment of metastases, and the effect of SerRS on metastasis can be independent of its impact on the primary tumor. SerRS also inhibits tumor growth with induced, post-tumor-onset overexpression, demonstrating its potential as an anticancer therapeutic. Tumor RNA-seq analysis identified Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To the best of our knowledge, this is the first study to show a component of the translation machinery can act as both a tumor and metastasis suppressor.
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Affiliation(s)
- Lei Jiang
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Justin Wang
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Ze Liu
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Qian Zhang
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Xiang-Lei Yang
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA
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Van Keymeulen A. Mechanisms of Regulation of Cell Fate in Breast Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:167-184. [PMID: 39821026 DOI: 10.1007/978-3-031-70875-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
This chapter focuses on the mechanisms of regulation of cell fate in breast development, occurring mainly after birth, as well as in breast cancer. First, we will review how the microenvironment of the breast, as well as external cues, plays a crucial role in mammary gland cell specification and will describe how it has been shown to reprogram non-mammary cells into mammary epithelial cells. Then we will focus on the transcription factors and master regulators which have been established to be determinant for basal (BC) and luminal cell (LC) identity, and will describe the experiments of ectopic expression or loss of function of these transcription factors which demonstrated that they were crucial for cell fate. We will also discuss how master regulators are involved in the fate choice of LCs between estrogen receptor (ER)-positive cells and ER- cells, which will give rise to alveolar cells upon pregnancy and lactation. We will describe how oncogene expression induces reprogramming and change of fate of mammary epithelial cells before tumor appearance, which could be an essential step in tumorigenesis. Finally, we will describe the involvement of master regulators of mammary epithelial cells in breast cancer.
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Affiliation(s)
- Alexandra Van Keymeulen
- Laboratory of Stem Cells and Cancer (LSCC), Université Libre de Bruxelles (ULB), Brussels, Belgium.
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Sethi S. Defining the Molecular Intricacies of Human Papillomavirus-Associated Tonsillar Carcinoma. Cancer Control 2025; 32:10732748241310932. [PMID: 40331509 PMCID: PMC12062609 DOI: 10.1177/10732748241310932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 05/08/2025] Open
Abstract
BackgroundThe past decade has shown a sharp incline in the human papillomavirus (HPV) infection associated oropharyngeal carcinoma cases, especially in men younger than 60 years old. Tonsils are one of the key sites, within the oropharyngeal region, which shows malignant changes due to HPV infection, and there is very limited literature to understand the specific dynamics in the tonsillar areas.ObjectiveThis critical review was undertaken to explore and unravel the bio-molecular interactions and the role of specific proteins associated with HPV infection induced tumorigenesis for the tonsils.DesignA systematic search of the literature was performed utilising keywords and MeSH terms related to HPV and tonsillar carcinoma in PubMed, Scopus, Embase, and Web of Science without restrictions on dates until July 2023. All studies that reported on molecular biomarkers or genes/genetic proteins in the context of HPV associated tonsillar carcinoma were included in the study.ResultsPreliminary searches revealed a total of 2734 studies of which 23 satisfied the final inclusion criteria and were included. More than 25 proteins and biomarkers were identified, and their role in the malignant process was extracted and compiled. This review also presents a short excerpt on each of the molecules identified to provide a better understanding of the pathogenesis.ConclusionGiven the rapidly increasing number of cases, there is an urgent need for more focused research on virally induced tonsillar cancers, to develop a better understanding, and for clarity of management and treatment.
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Affiliation(s)
- Sneha Sethi
- Adelaide Dental School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
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7
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Das A, Giri S, Dey P. Cell-cell junctional proteins in cancer. Adv Clin Chem 2024; 125:93-142. [PMID: 39988409 DOI: 10.1016/bs.acc.2024.11.006] [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: 02/25/2025]
Abstract
A hallmark change during carcinogenesis is disruption or dysregulation of cell-cell junctions. It enables a transformed cell to adopt mesenchymal phenotype and acquire higher potential to migrate and invade. This ultimately leads to cancer metastasis. During this process, junctional proteins undergo remarkable changes in terms of their expressional pattern, localization, and activity. De-localized junctional proteins may adopt atypical roles which might act to either suppress tumorigenesis or facilitate cancer development, depending on several factors. In this chapter, the authors attempt to know the expression pattern of junctional proteins in different types of cancer, understand its significance, and gather knowledge about the mechanisms by which they regulate tumorigenesis and cancer development.
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Affiliation(s)
- Aparajita Das
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
| | - Pubali Dey
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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Sakellakis M, Yoon SM, Reet J, Chalkias A. Novel insights into voltage-gated ion channels: Translational breakthroughs in medical oncology. Channels (Austin) 2024; 18:2297605. [PMID: 38154047 PMCID: PMC10761148 DOI: 10.1080/19336950.2023.2297605] [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: 10/10/2023] [Accepted: 12/05/2023] [Indexed: 12/30/2023] Open
Abstract
Preclinical evidence suggests that voltage gradients can act as a kind of top-down master regulator during embryogenesis and orchestrate downstream molecular-genetic pathways during organ regeneration or repair. Moreover, electrical stimulation shifts response to injury toward regeneration instead of healing or scarring. Cancer and embryogenesis not only share common phenotypical features but also commonly upregulated molecular pathways. Voltage-gated ion channel activity is directly or indirectly linked to the pathogenesis of cancer hallmarks, while experimental and clinical studies suggest that their modulation, e.g., by anesthetic agents, may exert antitumor effects. A large recent clinical trial served as a proof-of-principle for the benefit of preoperative use of topical sodium channel blockade as a potential anticancer strategy against early human breast cancers. Regardless of whether ion channel aberrations are primary or secondary cancer drivers, understanding the functional consequences of these events may guide us toward the development of novel therapeutic approaches.
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Affiliation(s)
- Minas Sakellakis
- Department of Medicine, Jacobi North Central Bronx Hospital, Bronx, USA
| | - Sung Mi Yoon
- Department of Medicine, Jacobi North Central Bronx Hospital, Bronx, USA
| | - Jashan Reet
- Department of Medicine, Jacobi North Central Bronx Hospital, Bronx, USA
| | - Athanasios Chalkias
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Outcomes Research Consortium, Cleveland, OH, USA
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Wang J, Zhang W, Zhang R, Yang H, Li Y, Wang J, Li C. MiR-101-3p Promotes Tumor Cell Proliferation and Migration via the Wnt Signal Pathway in MNNG-Induced Esophageal Squamous Cell Carcinoma. TOXICS 2024; 12:824. [PMID: 39591002 PMCID: PMC11598764 DOI: 10.3390/toxics12110824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024]
Abstract
N-methyl-n'-nitroso-n'-nitroso guanidine (MNNG) can induce esophageal squamous cell carcinoma (ESCC), and microRNAs are associated with the development of ESCC and may serve as potential tumor prognostic markers. Thus, the aim of this study was to evaluate the potential function of miR-101-3p in MNNG-induced ESCC. An investigation of risk factors in patients with ESCC was carried out and the concentration of nine nitrosamines in urine samples was detected by the SPE-GC-MS technique. Then, we performed cancer tissue gene sequencing analysis, and RT-qPCR verified the expression level of miR-101-3p. Subsequently, the relationship between miR-101-3p potential target genes and the ESCC patients' prognosis was predicted. Finally, we investigated the function of miR-101-3p in MNNG-induced ESCC pathogenesis and the regulatory mechanism of the signaling pathway by in vivo and in vitro experiments. The results revealed that high dietary nitrosamine levels are high-risk factors for ESCC. MiR-101-3p is down-regulated in ESCC tissues and cells, and its potential target genes are enriched in cell migration and cancer-related pathways. MiR-101-3p target genes include AXIN1, CK1, and GSK3, which are involved in the regulation of the Wnt signaling pathway. MiR-101-3p overexpression promotes apoptosis and inhibits the proliferation and migration of Eca109 cells. The Wnt pathway is activated after subchronic exposure to MNNG, and the Wnt pathway is inhibited by the overexpression of miR-101-3p in Eca109 cells. Down-regulated miR-101-3p may exert tumor suppressive effects by regulating the Wnt pathway and may be a useful biomarker for predicting ESCC progression.
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Affiliation(s)
- Jianding Wang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China; (J.W.); (W.Z.); (Y.L.); (J.W.)
| | - Wenwen Zhang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China; (J.W.); (W.Z.); (Y.L.); (J.W.)
| | - Rui Zhang
- Key Laboratory for Reproductive Medicine and Embryo, The Reproductive Medicine Special Hospital of the Lanzhou University First Affiliated Hospital, Lanzhou 730000, China;
| | - Hanteng Yang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China;
| | - Yitong Li
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China; (J.W.); (W.Z.); (Y.L.); (J.W.)
| | - Junling Wang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China; (J.W.); (W.Z.); (Y.L.); (J.W.)
| | - Chengyun Li
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China; (J.W.); (W.Z.); (Y.L.); (J.W.)
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10
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Zasheva D, Mladenov P, Zapryanova S, Gospodinova Z, Georgieva M, Alexandar I, Velinov V, Djilianov D, Moyankova D, Simova-Stoilova L. Cytotoxic Effects of Plant Secondary Metabolites and Naturally Occurring Bioactive Peptides on Breast Cancer Model Systems: Molecular Mechanisms. Molecules 2024; 29:5275. [PMID: 39598664 PMCID: PMC11596968 DOI: 10.3390/molecules29225275] [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: 09/30/2024] [Revised: 10/30/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Breast cancer is the second leading cause of death among women, and the number of mortal cases in diagnosed patients is constantly increasing. The search for new plant compounds with antitumor effects is very important because of the side effects of conventional therapy and the development of drug resistance in cancer cells. The use of plant substances in medicine has been well known for centuries, but the exact mechanism of their action is far from being elucidated. The molecular mechanisms of cytotoxicity exerted by secondary metabolites and bioactive peptides of plant origin on breast cancer cell lines are the subject of this review.
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Affiliation(s)
- Diana Zasheva
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Petko Mladenov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Silvina Zapryanova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Zlatina Gospodinova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Mariyana Georgieva
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Irina Alexandar
- Institute of Molecular Biology “Rumen Tzanev”, Bulgarian Academy of Sciences, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria;
| | - Valentin Velinov
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Dimitar Djilianov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Daniela Moyankova
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Lyudmila Simova-Stoilova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
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Jeong JS, Baek GH, Kim JW, Kim JH, Chung EH, Ko JW, Kwon MJ, Kim SK, Lee SH, Kim JS, Kim TW. Korean Red Ginseng alleviates dextran sodium sulfate-induced colitis through gut microbiota modulation in mice. J Ginseng Res 2024; 48:581-591. [PMID: 39583173 PMCID: PMC11584195 DOI: 10.1016/j.jgr.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/25/2024] [Accepted: 08/08/2024] [Indexed: 11/26/2024] Open
Abstract
Background There is a growing interest in understanding the association between the gut microbiota and inflammatory bowel disease (IBD). Natural compounds, such as Korean Red Ginseng (KRG), show promise for IBD treatment because of their ability to influence gut microbiota. This study explored the effects of KRG on gut microbiota modulation and subsequent intestinal epithelial cell regeneration in an experimental colitis model. Method Using a mouse model of colitis induced by 2 % dextran sodium sulfate, the study administered 200 or 400 mg/kg/day of KRG to evaluate its biological effects. Colitis symptoms were assessed through body weight, disease activity index, colon length, and histological analysis. The microbial composition in the fecal was determined using 16S rRNA sequencing. To evaluate regeneration signals in the colon, western blotting and immunohistochemistry assays were conducted. Result Administration of KRG effectively mitigated colitis symptoms in mice, as indicated by histological examination showing alleviated epithelial damage and inflammation, along with increased mucus production. Microbiota analysis showed that KRG significantly altered microbial diversity, favoring beneficial taxa and suppressing harmful taxa. Moreover, ameliorated β-catenin/transcription factor-4 protein expression, a key signal associated with epithelial cell regeneration, was observed in the KRG treated groups, accompanied by improved intestinal linings. Conclusion These findings suggest that KRG exerts biological effects in colitis by modulating gut microbiota and creating a favorable intestinal environment, thereby reducing regenerative signals. Further research is warranted to elucidate the cellular and molecular mechanisms underlying the interaction of KRG with gut microbiota and pave the way for effective IBD therapies.
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Affiliation(s)
- Ji-Soo Jeong
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Ga-Hyeon Baek
- Department of Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea
| | - Jeong-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Jin-Hwa Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Eun-Hye Chung
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Mi-Jin Kwon
- R&D Headquarters, Korea Ginseng Corporation, Gwacheon, Republic of Korea
| | - Sang-Kyu Kim
- R&D Headquarters, Korea Ginseng Corporation, Gwacheon, Republic of Korea
| | - Seung-Ho Lee
- R&D Headquarters, Korea Ginseng Corporation, Gwacheon, Republic of Korea
| | - Jun-Seob Kim
- Department of Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea
- Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, Incheon, Republic of Korea
| | - Tae-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
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12
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Yang R, Pray B, Alinari L, Li PK, Cheng X. Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders. ACS Med Chem Lett 2024; 15:1699-1707. [PMID: 39411529 PMCID: PMC11472461 DOI: 10.1021/acsmedchemlett.4c00255] [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: 06/04/2024] [Revised: 09/21/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by TD11 relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.
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Affiliation(s)
- Rui Yang
- Division
of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Betsy Pray
- Division
of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, United States
| | - Lapo Alinari
- Division
of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, United States
| | - Pui Kai Li
- Division
of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
| | - Xiaolin Cheng
- Division
of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
- Translational
Data Analytics Institute, The Ohio State
University, Columbus, Ohio 43210, United States
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13
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Lim HY, Dolzhenko AV. 1,3,5-Triazine as a promising scaffold in the development of therapeutic agents against breast cancer. Eur J Med Chem 2024; 276:116680. [PMID: 39018924 DOI: 10.1016/j.ejmech.2024.116680] [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: 05/02/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
1,3,5-Triazine scaffold has garnered considerable interest due to its wide-ranging pharmacological properties, particularly in the field of cancer research. Breast cancer is the most commonly diagnosed cancer among women. Approximately one in eight women will receive a diagnosis of invasive breast cancer during their lifetime. The five-year survival rate for invasive breast cancer is less than 30 %, indicating a need to develop a more effective therapeutic agent targeting breast cancer. This review discusses bioactive 1,3,5-triazines targeting breast cancer cells by the inhibition of different enzymes, which include PI3K, mTOR, EGFR, VEGFR, FAK, CDK, DHFR, DNA topoisomerase, ubiquitin-conjugating enzyme, carbonic anhydrase, and matrix metalloproteinase. The anticancer agent search in some drug discovery programs is based on compound screening for antiproliferative activity. Often, multiple targets contribute to the anticancer effect of 1,3,5-triazines and this approach allows identification of active molecules prior to identification of their targets.
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Affiliation(s)
- Han Yin Lim
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia.
| | - Anton V Dolzhenko
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; Curtin Medical School, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987 Perth, Western, Bentley, 6845, Australia
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14
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Hansen E, Rolling C, Wang M, Holaska JM. Emerin deficiency drives MCF7 cells to an invasive phenotype. Sci Rep 2024; 14:19998. [PMID: 39198511 PMCID: PMC11358522 DOI: 10.1038/s41598-024-70752-5] [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: 03/05/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer cells showed similar results. Supporting the clinical relevance of emerin reduction in cancer progression, our analysis of 192 breast cancer patient samples showed emerin expression inversely correlates with cancer invasiveness. We conclude emerin loss is an important driver of invasive transformation and has utility as a biomarker for tumor progression.
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Affiliation(s)
- Emily Hansen
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, MEB 534, 401 South Broadway, Camden, NJ, 08103, USA
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ, 08084, USA
| | - Christal Rolling
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, MEB 534, 401 South Broadway, Camden, NJ, 08103, USA
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ, 08084, USA
| | - Matthew Wang
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, MEB 534, 401 South Broadway, Camden, NJ, 08103, USA
- Rowan-Virtua School of Osteopathic Medicine, Stratford, NJ, 08084, USA
| | - James M Holaska
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, MEB 534, 401 South Broadway, Camden, NJ, 08103, USA.
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ, 08084, USA.
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15
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Martinez S, Sentis S, Poulard C, Trédan O, Le Romancer M. Role of PRMT1 and PRMT5 in Breast Cancer. Int J Mol Sci 2024; 25:8854. [PMID: 39201539 PMCID: PMC11354362 DOI: 10.3390/ijms25168854] [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: 07/10/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/02/2024] Open
Abstract
Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70-80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity of breast carcinogenesis is often associated with epigenetic modification regulating different signaling pathways, involved in breast tumor initiation and progression, particularly by the methylation of arginine residues. Protein arginine methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones and non-histone substrates, as essential regulators of cancers. Here, we present an updated overview of the mechanisms by which PRMT1 and PRMT5, two major members of the PRMT family, control important signaling pathways impacting breast tumorigenesis, highlighting them as putative therapeutic targets.
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Affiliation(s)
- Sébastien Martinez
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
| | - Stéphanie Sentis
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
| | - Coralie Poulard
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
| | - Olivier Trédan
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- Oncology Department, Centre Leon Bérard, F-69008 Lyon, France
| | - Muriel Le Romancer
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, F-69000 Lyon, France
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16
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Hansen E, Rolling C, Wang M, Holaska JM. Emerin deficiency drives MCF7 cells to an invasive phenotype. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.21.581379. [PMID: 38712242 PMCID: PMC11071294 DOI: 10.1101/2024.02.21.581379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer cells showed similar results. Supporting the clinical relevance of emerin reduction in cancer progression, our analysis of 192 breast cancer patient samples showed emerin expression inversely correlates with cancer invasiveness. We conclude emerin loss is an important driver of invasive transformation and has utility as a biomarker for tumor progression.
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Affiliation(s)
- Emily Hansen
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ
| | - Christal Rolling
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ
| | - Matthew Wang
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ
- Rowan-Virtua School of Osteopathic Medicine
| | - James M. Holaska
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ
- Molecular and Cell Biology and Neuroscience Program, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ
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17
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Saliu TP, Seneviratne NN, Faizan M, Rajagopalan U, Perera DC, Adhikari A, Senathilake KS, Galhena P, Tennekoon KH, Samarakoon SR. In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/β-catenin signaling pathway in breast cancer stem cells. In Silico Pharmacol 2024; 12:31. [PMID: 38617708 PMCID: PMC11014832 DOI: 10.1007/s40203-024-00199-z] [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: 11/14/2023] [Accepted: 02/19/2024] [Indexed: 04/16/2024] Open
Abstract
Cancer stem cells (CSCs) play a vital role in metastasis, recurrence and chemoresistance in breast cancer. β-catenin, which is a frequently over activated protein in CSCs, binds to T-cell factor/lymphoid enhancer factor (Tcf/Lef) family transcription factors leading to ectopic expression of Wnt pathway responsive genes necessary for the maintenance and action of CSCs. With the aim of identifying a small molecules that can effectively eliminate CSCs, molecular docking studies were performed against the Tcf/Lef binding hotspot on β-catenin using a library of 100 natural or synthetic small molecules. Small molecule ligands giving docking energy better than - 7 kcal/mol were further investigated by binding interactions analysis and molecular dynamics (MD) simulations. These compounds were then investigated in vitro, for cytotoxicity against CSCs isolated from MDA-MB-231 triple negative breast cancer cells. Alpha-hederin (AH) was identified as the only compound in the selected library that has cytotoxicity against breast CSCs. AH was further investigated for it's ability to regulate Wnt pathway target genes (Cyclin D1 and CD44)and the tumor suppressor p53by real-time quantitative PCR. Absorption, distribution, metabolism, excretion and toxicity properties of the AH was predicted in silico. AH significantly down regulated the transcription of Cyclin D1 and CD44 while up-regulating the transcription of p53. AH was predicted to have acceptable drug likeness. Although AH is currently known to inhibit the growth of various cancer cells in vitro, present study demonstrated for the first time that it is a potent inhibitor of Wnt/β-catenin signaling pathway and induce apoptosis in breast CSCs.
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Affiliation(s)
- Tolulope Peter Saliu
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Nirwani Natasha Seneviratne
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Mishal Faizan
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Umapriyatharshini Rajagopalan
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Damith Chathuranga Perera
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Achyut Adhikari
- Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal
| | - Kanishka Sithira Senathilake
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Prasanna Galhena
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Kamani Hemamala Tennekoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Sameera Ranganath Samarakoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
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18
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Hemida AS, Shabaan MI, Taha MA, Abdou AG. Impact of immunohistochemical expression of kinesin family member 18A (Kif18A) and β-catenin in infiltrating breast carcinoma of no special type. World J Surg Oncol 2024; 22:15. [PMID: 38195458 PMCID: PMC10777553 DOI: 10.1186/s12957-023-03276-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/09/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND KIF18A is a regulator of the cell cycle that stimulates the proliferation of cancer cells. The Wnt/β-catenin pathway is involved in different issues' carcinogenesis and is being examined as a therapeutic target. The relationship between KIF18A and β-catenin in breast cancer was not previously investigated. Therefore, this work aims to study the immunohistochemical expression and correlation of KIF18A and β-catenin in breast-infiltrating duct carcinoma (IDC) and their relation to prognosis. MATERIAL AND METHODS Slides cut from paraffin blocks of 135 IDC and 40 normal breast tissues were stained by KIF18A and β-catenin antibodies. KIF18A cytoplasmic or nucleocytoplasmic staining and β-catenin aberrant expression either nucleo-cytoplasmic or cytoplasmic staining were considered. RESULTS Normal breast tissue and IDC showed a significant difference regarding KIF18A and aberrant β-catenin expression. High KIF18A and β-catenin H score values were associated with poor prognostic factors such as high grade, advanced stage, distant metastasis, high Ki67 status, and Her2neu-enriched subtype. There was a significant direct correlation between KIF18A and β-catenin as regards percent and H score values. Prolonged overall survival (OS) was significantly associated with mild intensity and low H score of KIF18A, and low β-catenin H score. CONCLUSIONS KIF18A could be involved in breast carcinogenesis by activating β-catenin. Overexpression of KIF18A and aberrant expression of β-catenin are considered proto-oncogenes of breast cancer development. KIF18A and β-catenin could be poor prognostic markers and predictors of aggressive behavior of breast cancer.
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Affiliation(s)
- Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt.
| | - Mohammed Ibrahim Shabaan
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
| | - Mennatallah Ahmed Taha
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
| | - Asmaa Gaber Abdou
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
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19
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Dev A, Vachher M, Prasad CP. β-catenin inhibitors in cancer therapeutics: intricacies and way forward. Bioengineered 2023; 14:2251696. [PMID: 37655825 PMCID: PMC10478749 DOI: 10.1080/21655979.2023.2251696] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023] Open
Abstract
β-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. β-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant β-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. β-catenin's expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of β-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of β-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting β-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.
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Affiliation(s)
- Arundhathi Dev
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
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20
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Rodgers SJ, Mitchell CA, Ooms LM. The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer. Biochem Soc Trans 2023; 51:1459-1472. [PMID: 37471270 PMCID: PMC10586779 DOI: 10.1042/bst20220866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/08/2023] [Accepted: 07/05/2023] [Indexed: 07/22/2023]
Abstract
The class IA PI3K signaling pathway is activated by growth factor stimulation and regulates a signaling cascade that promotes diverse events including cell growth, proliferation, migration and metabolism. PI3K signaling is one of the most commonly hyperactivated pathways in breast cancer, leading to increased tumor growth and progression. PI3K hyperactivation occurs via a number of genetic and epigenetic mechanisms including mutation or amplification of PIK3CA, the gene encoding the p110α subunit of PI3Kα, as well as via dysregulation of the upstream growth factor receptors or downstream signaling effectors. Over the past decade, extensive efforts to develop therapeutics that suppress oncogenic PI3K signaling have been undertaken. Although FDA-approved PI3K inhibitors are now emerging, their clinical success remains limited due to adverse effects and negative feedback mechanisms which contribute to their reduced efficacy. There is an emerging body of evidence demonstrating crosstalk between the PI3K and Wnt/β-catenin pathways in breast cancer. However, PI3K exhibits opposing effects on Wnt/β-catenin signaling in distinct tumor subsets, whereby PI3K promotes Wnt/β-catenin activation in ER+ cancers, but paradoxically suppresses this pathway in ER- breast cancers. This review discusses the molecular mechanisms for PI3K-Wnt crosstalk in breast cancer, and how Wnt-targeted therapies have the potential to contribute to treatment regimens for breast cancers with PI3K dysregulation.
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Affiliation(s)
- Samuel J. Rodgers
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Christina A. Mitchell
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Lisa M. Ooms
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
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21
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Alsaab HO. Pathological role of long non-coding (lnc) RNA in the regulation of Wnt/β-catenin signaling pathway during epithelial-mesenchymal transition (EMT). Pathol Res Pract 2023; 248:154566. [PMID: 37285735 DOI: 10.1016/j.prp.2023.154566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/09/2023]
Abstract
The term "epithelial-mesenchymal transition" (EMT) describes a biological process wherein epithelial cells acquire mesenchymal cell characteristics. This process enables the metastatic cells to migrate and invasion. Recent studies have established the connections between the EMT process and Wnt/β-catenin signaling in cancer. Key cellular functions such as differentiation, proliferation, migration, genetic stability, apoptosis, and stem cell renewal are modulated via Wnt/ β-catenin signaling pathway. Up-regulation of this evolutionarily conserved signal pathway leads to EMT. On the other hand, recent investigations have indicated that non-coding RNAs including microRNAs (miRNAs) and long non-coding RNA (lncRNAs) are involved in regulating of Wnt/β-catenin pathway. A high level of lncRNAs mainly has a positive correlation with EMT. However, lncRNA down-regulation has been observed in promoting EMT. It seems that depending on the specific targets, up-or down-regulation of lncRNAs can stimulate EMT by activating the Wnt/ β-catenin pathway. The evaluation of interactions between lncRNAs and the Wnt/ β-catenin signaling pathway in the regulation of EMT during metastasis can be fascinating. Herein, for the first time, the crucial role of lncRNAs-mediated regulation of the Wnt/ β-catenin signaling pathway in the EMT process of human tumors has been summarized.
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Affiliation(s)
- Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia.
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22
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Sanchez N, Harvey C, Vincent D, Croft J, Zhang J. Biomarkers derived from CmP signal network in triple negative breast cancers. TRANSLATIONAL BREAST CANCER RESEARCH : A JOURNAL FOCUSING ON TRANSLATIONAL RESEARCH IN BREAST CANCER 2023; 4:21. [PMID: 38751477 PMCID: PMC11093088 DOI: 10.21037/tbcr-23-30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/25/2023] [Indexed: 05/18/2024]
Abstract
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women, accounting for approximately 30% of all new cancer cases. The prognosis of breast cancer heavily depends on the stage of diagnosis, with early detection resulting in higher survival rates. Various risk factors, including family history, alcohol consumption and hormone exposure, contribute to breast cancer development. Triple-negative breast cancer (TNBC), characterized by the absence of certain receptors, is particularly aggressive and heterogeneous. Cerebral cavernous malformations (CCMs), abnormal dilations of small blood vessels in the brain, is contributed by mutated genes like CCM1, CCM2, and CCM3 through the perturbed formation of the CCM signaling complex (CSC). The CSC-non-classic membrane progesterone receptors (mPRs)-progesterone (PRG) (CmP)/CSC-mPRs-PRG-classic nuclear progesterone receptors (nPRs) (CmPn) signaling network, which integrates the CSC with mPRs and nPRs, plays a role in breast cancer tumorigenesis. Understanding these pathways can provide insights into potential treatments. This paper focuses on the emerging field of CmPn/CmP signal networks, which involve PRG, its receptors (nPRs and mPRs), and the CSC. These networks play a role in tumorigenesis, particularly in TNBCs. Aims to deliver a thorough examination of the CmP/CmPn pathways concerning TNBCs, this paper provides a comprehensive overview of these pathways, explores their applications and highlights their significance in the context of TNBCs.
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Affiliation(s)
- Nickolas Sanchez
- Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, USA
| | - Charles Harvey
- Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, USA
| | - Drexell Vincent
- Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, USA
| | - Jacob Croft
- Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, USA
| | - Jun Zhang
- Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX, USA
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23
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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24
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Tang Y, Lin TC, Kim YC, Chung S, Liu Z. High-Fat Diet Exposure in Early Life Alters Mammary Metabolic and Inflammatory Microenvironment in Favor of Breast Tumorigenesis Later in Life in Mice. Curr Oncol 2023; 30:4197-4207. [PMID: 37185433 PMCID: PMC10136975 DOI: 10.3390/curroncol30040320] [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: 03/15/2023] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Emerging evidence highlights the important impact of early-life exposures on cancer development later in life. The present study aimed to investigate the impacts of a high-fat diet in early life on the mammary microenvironment in relation to breast tumorigenesis. Forty-four female C57BL/6 mice were fed a low-fat diet (LF, 10 kcal% fat) or a high-fat diet (HF, 60 kcal% fat) for 8 weeks starting at ~4 weeks of age. Twenty-two mice were sacrificed immediately after an 8 week feeding, and the rest of mice were switched to a normal diet for maintenance (Lab Diet, #5P76) for additional 12 weeks. A panel of metabolic parameters, inflammatory cytokines, as well as tumorigenic Wnt-signaling target genes were analyzed. The HF diet increased body weight and exacerbated mammary metabolic and inflammatory status. The disrupted microenvironment remains significant to the later life equivalent to young adulthood (p < 0.05). Mammary Wnt-signaling was elevated right after the HF diet as indicated by the upregulated expression of its downstream genes, whereas it was surprisingly suppressed after switching diets (p < 0.05). In summary, HF-induced overweight/obesity in early life altered the mammary metabolic and inflammatory microenvironments in favor of breast tumorigenesis, although its overall impact to breast cancer later in life warrants further investigation.
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Affiliation(s)
- Ying Tang
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Ting-Chun Lin
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Young-Cheul Kim
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Soonkyu Chung
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Zhenhua Liu
- Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
- UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
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Wu T, Zhu D, Wu X, Zhang N, Zhang Q. Taxol‑resistant breast cancer cell‑derived exosome‑delivered miR‑187‑5p regulates the growth of breast cancer cells via ABCD2 and Wnt/β‑catenin signaling. Oncol Lett 2023; 25:119. [PMID: 36844629 PMCID: PMC9950341 DOI: 10.3892/ol.2023.13705] [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: 08/29/2022] [Accepted: 01/24/2023] [Indexed: 02/10/2023] Open
Abstract
Acquired resistance to Taxol (TAX) contributes to clinical treatment failure and significantly reduces the survival rate of patients. The present study aimed to explore the effects of exosomal microRNA (miR)-187-5p on TAX resistance in breast cancer cells and its underlying mechanisms. Exosomes were isolated from MCF-7 and TAX-resistant MCF-7/TAX cells, and the miR-187-5p and miR-106a-3p levels of the cells and exosomes were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Next, MCF-7 cells were treated with TAX for 48 h and either treated with exosomes or transfected with miR-187-5p mimics. Cell viability, apoptosis, migration, invasion and colony formation were determined using Cell Counting Kit-8, flow cytometry, Transwell and colony formation assays, and the expression levels of associated genes and proteins were detected by RT-qPCR and western blotting, respectively. Finally, a dual-luciferase reporter gene assay was performed to confirm the target of miR-187-5p. The results showed that miR-187-5p expression levels increased significantly in TAX-resistant MCF-7 cells and exosomes compared with normal MCF-7 cells and exosomes (P<0.05). However, miR-106a-3p was not detected in the cells or exosomes. Therefore, miR-187-5p was selected for subsequent experiments. A series of cell assays showed that TAX inhibited the viability, migration, invasion and colony formation of MCF-7 cells and promoted their apoptosis; however, these changes were reversed by resistant cell exosomes and miR-187-5p mimics. Additionally, TAX significantly upregulated ABCD2 and downregulated β-catenin, c-Myc and cyclin D1, whereas resistant exosomes and miR-187-5p mimics reversed the TAX-induced changes in expression. Finally, ABCD2 was confirmed to directly bind with miR-187-5p. It may be concluded that TAX-resistant cell-derived exosomes delivering miR-187-5p may affect the growth of TAX-induced breast cancer cells by targeting ABCD2 and c-Myc/Wnt/β-catenin signaling.
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Affiliation(s)
- Tieli Wu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Dandan Zhu
- Department of Medical Oncology, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China
| | - Xingyi Wu
- Department of Internal Medicine, Qiqihar First Factory Hospital, Qiqihar, Heilongjiang 161000, P.R. China
| | - Ningning Zhang
- School of Basic Medicine, Qiqihar Medical University, Qiqihar, Heilongjiang 161000, P.R. China
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
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Ouban A, Ameer OZ, Quek KJ, Arafah MA, Raddaoui L. Detection of Increased Expression of Claudin-1 in Triple-Negative Breast Cancer: Analysis and Clinical-Pathological Correlation. Cureus 2023; 15:e36648. [PMID: 37102018 PMCID: PMC10123009 DOI: 10.7759/cureus.36648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2023] [Indexed: 04/28/2023] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a highly aggressive disease that lacks therapeutic targets and prognostic biomarkers. Claudin-1 is a well-described tight junction protein with prognostic value in many human cancers. Aims The need for the discovery of biomarkers of TNBC disease was a major reason for this study. Claudin-1 is a tight junction protein that has shown promising results in the prognosis and management of cancer in general. In the breast, claudin-1 expression and significance have shown variable results, especially in TNBC patients. Our study assessed expression of claudin-1 in a group of TNBC patients, and correlated this expression with clinical-pathological parameters, and with the expression of β-catenin. Materials and methods Tissues from a group of 52 TNBC patients were retrieved from the archives of the community hospital. All related information including demographical, pathologic and clinical data were retrieved. Immunohistochemistry assays of a rabbit polyclonal antibody anti-human claudin-1 were applied using the avidin-biotin peroxidase methodology. Results A statistically significant majority of TNBC cases positively expressed claudin-1 (81%, χ2=13.705; p<0.001). Most TNBC cases had grade 2 β-catenin expression (77.5%; p<0.001), and positive expression for claudin-1 correlated with that of β-catenin (χ2= 23.757; p<0.001). Claudin-1 and β-catenin expressions within tumour cells shared several features including absent or weakness of membranous expression, and redistribution of both proteins to the cytoplasm of tumour cells, and in some cases to the nuclei of these cells. Claudin-1 expression also correlates with adverse survival outcomes, where only four of 20 claudin-1-positive patients who received neo-adjuvant chemotherapy (NAC) achieved pathological complete response (pCR). Conclusions The above presents a complex role of claudin-1 in TNBC patients. In this study, claudin-1 expression was associated with poor prognostic features including invasion, metastases and adverse clinical outcomes. Claudin-1 expression in TNBC correlated with the expression of β-catenin, an important oncogene and a major contributor to the epithelial mesenchymal transition (EMT) phenomenon. Overall, the above results may serve as an impetus for further mechanistic studies to assess the exact role of claudin-1 in TNBC and its possible use in the management of this subset of breast cancer.
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Affiliation(s)
- Abderrahman Ouban
- Pathology and Molecular Medicine, Alfaisal University College of Medicine, Riyadh, SAU
| | - Omar Z Ameer
- Pharmaceutical Sciences, Alfaisal University College of Pharmacy, Riyadh, SAU
| | - Ko Jin Quek
- Family Medicine, Faculty of Biomedical Sciences, Macquarie University, Sydney, AUS
| | - Maria A Arafah
- Pathology and Laboratory Medicine, King Saud University, Riyadh, SAU
| | - Layla Raddaoui
- Oncology, Alfaisal University College of Medicine, Riyadh, SAU
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Kaiser A, Eiselt G, Bechler J, Huber O, Schmidt M. WNT3a Signaling Inhibits Aromatase Expression in Breast Adipose Fibroblasts-A Possible Mechanism Supporting the Loss of Estrogen Responsiveness of Triple-Negative Breast Cancers. Int J Mol Sci 2023; 24:ijms24054654. [PMID: 36902090 PMCID: PMC10003471 DOI: 10.3390/ijms24054654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/04/2023] Open
Abstract
Estrogen-dependent breast cancers rely on a constant supply of estrogens and expression of estrogen receptors. Local biosynthesis, by aromatase in breast adipose fibroblasts (BAFs), is their most important source for estrogens. Triple-negative breast cancers (TNBC) rely on other growth-promoting signals, including those from the Wnt pathway. In this study, we explored the hypothesis that Wnt signaling alters the proliferation of BAFs, and is involved in regulation of aromatase expression in BAFs. Conditioned medium (CM) from TNBC cells and WNT3a consistently increased BAF growth, and reduced aromatase activity up to 90%, by suppression of the aromatase promoter I.3/II region. Database searches identified three putative Wnt-responsive elements (WREs) in the aromatase promoter I.3/II. In luciferase reporter gene assays, promoter I.3/II activity was inhibited by overexpression of full-length T-cell factor (TCF)-4 in 3T3-L1 preadipocytes, which served as a model for BAFs. Full-length lymphoid enhancer-binding factor (LEF)-1 increased the transcriptional activity. However, TCF-4 binding to WRE1 in the aromatase promoter, was lost after WNT3a stimulation in immunoprecipitation-based in vitro DNA-binding assays, and in chromatin immunoprecipitation (ChIP). In vitro DNA-binding assays, ChIP, and Western blotting revealed a WNT3a-dependent switch of nuclear LEF-1 isoforms towards a truncated variant, whereas β-catenin levels remained unchanged. This LEF-1 variant revealed dominant negative properties, and most likely recruited enzymes involved in heterochromatin formation. In addition, WNT3a induced the replacement of TCF-4 by the truncated LEF-1 variant, on WRE1 of the aromatase promoter I.3/II. The mechanism described here may be responsible for the loss of aromatase expression predominantly associated with TNBC. Tumors with (strong) expression of Wnt ligands actively suppress aromatase expression in BAFs. Consequently a reduced estrogen supply could favor the growth of estrogen-independent tumor cells, which consequently would make estrogen receptors dispensable. In summary, canonical Wnt signaling within (cancerous) breast tissue may be a major factor controlling local estrogen synthesis and action.
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Affiliation(s)
- Alexander Kaiser
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Gabriele Eiselt
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Joachim Bechler
- Department of Gynecology and Obstetrics, Robert-Koch-Hospital, 99510 Apolda, Germany
| | - Otmar Huber
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Martin Schmidt
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
- Correspondence: ; Tel.: +49-3641-939-6420
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28
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Shen LA, Peng X, Bao Y, Liu C, Zhang H, Li J, Zhu D, Zhang Q. Design, synthesis and biological evaluation of quercetin derivatives as novel β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors. Eur J Med Chem 2023; 247:115075. [PMID: 36599228 DOI: 10.1016/j.ejmech.2022.115075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 12/08/2022] [Accepted: 12/29/2022] [Indexed: 01/02/2023]
Abstract
The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on β-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with β-catenin and disrupted the β-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/β-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore β-catenin-related biology and a drug-like quercetin derivative as novel β-catenin/BCL9 PPI inhibitors for further drug development.
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Affiliation(s)
- Li-An Shen
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Xinyan Peng
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Ya Bao
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Chenglong Liu
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Hao Zhang
- School of Pharmacy, Fudan University, Shanghai, 201203, China; Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Jianqi Li
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Di Zhu
- School of Pharmacy, Fudan University, Shanghai, 201203, China; Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai, 201100, China.
| | - Qingwei Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
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29
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Selvarathinam K, Subramani P, Thekkumalai M, Vilwanathan R, Selvarajan R, Abia ALK. Wnt Signaling Pathway Collapse upon β-Catenin Destruction by a Novel Antimicrobial Peptide SKACP003: Unveiling the Molecular Mechanism and Genetic Activities Using Breast Cancer Cell Lines. Molecules 2023; 28:molecules28030930. [PMID: 36770598 PMCID: PMC9920962 DOI: 10.3390/molecules28030930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Despite progress in breast cancer treatment, the survival rate for patients with metastatic breast cancer remains low due to chemotherapeutic agent resistance and the lack of specificity of the current generation of cancer drugs. Our previous findings indicated that the antimicrobial peptide SKACP003 exhibited anticancer properties, particularly against the MCF-7, MDA-MB-231, and MDA-MB-453 breast cancer cell lines. However, the mechanism of SKACP003-induced cancer cell death is unknown. Here, we investigated the molecular mechanism by which SKACP003 inhibits the cell cycle, cell proliferation, and angiogenesis in breast cancer cell lines. The results revealed that all the breast cancer cell lines treated at their IC50 values significantly inhibited the replicative phase of the cell cycle. The SKACP003-induced growth inhibition induced apoptosis, as evidenced by a decrease in BCL-2 and an increase in BAX and caspase gene (Cas-3, Cas-8, and Cas-9) expression. Reduced expression of the β-Catenin signaling pathway was associated with the SKACP003-induced apoptosis. SKACP003-treated breast cancer cells showed decreased expression of Wnt/β-Catenin targeting genes such as C-Myc, P68, and COX-2 and significant downregulation of CDK-4 and CDK-6 genes. Furthermore, cytoplasmic β-catenin protein levels in SKACP003-treated cell lines were significantly lower than in control cell lines. The results of the current study suggest that the newly identified antimicrobial peptide SKACP003 has great potential as a candidate for specifically targeting the β-catenin and thus significantly reducing the progression and prognosis of breast cancer cell lines.
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Affiliation(s)
- Kanitha Selvarathinam
- Department of Biochemistry, J.J. College of Arts and Science (Autonomous), Pudukkottai 622422, Tamilnadu, India
- Correspondence: (K.S.); (A.L.K.A.)
| | - Prabhu Subramani
- Department of Biochemistry, School of Life Science, Bharathidasan University, Tiruchirappalli 622422, Tamilnadu, India
| | | | - Ravikumar Vilwanathan
- Department of Biochemistry, School of Life Science, Bharathidasan University, Tiruchirappalli 622422, Tamilnadu, India
| | - Ramganesh Selvarajan
- Department of Environmental Sciences, College of Agricultural and Environmental Sciences (CAES), University of South Africa (UNISA), Florida—Campus, Florida Park, Roodepoort 1709, South Africa
- Laboratory of Extraterrestrial Ocean Systems (LEOS), Institute of Deep-Sea Science and Engineering, Chinese Academy of Sciences (CAS), Sanya 572000, China
| | - Akebe Luther King Abia
- Department of Environmental Sciences, College of Agricultural and Environmental Sciences (CAES), University of South Africa (UNISA), Florida—Campus, Florida Park, Roodepoort 1709, South Africa
- Environmental Research Foundation, Westville 3630, South Africa
- Correspondence: (K.S.); (A.L.K.A.)
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PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer. Int J Mol Sci 2023; 24:ijms24010882. [PMID: 36614323 PMCID: PMC9821466 DOI: 10.3390/ijms24010882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/23/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Past studies have confirmed that aberrant activation of the Wnt/β-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and β-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of β-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous β-catenin. PLA2G7 silencing provoked the β-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer.
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Zangouei AS, Zangoue M, Taghehchian N, Zangooie A, Rahimi HR, Saburi E, Alavi MS, Moghbeli M. Cell cycle related long non-coding RNAs as the critical regulators of breast cancer progression and metastasis. Biol Res 2023; 56:1. [PMID: 36597150 PMCID: PMC9808980 DOI: 10.1186/s40659-022-00411-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/29/2022] [Indexed: 01/04/2023] Open
Abstract
Cell cycle is one of the main cellular mechanisms involved in tumor progression. Almost all of the active molecular pathways in tumor cells directly or indirectly target the cell cycle progression. Therefore, it is necessary to assess the molecular mechanisms involved in cell cycle regulation in tumor cells. Since, early diagnosis has pivotal role in better cancer management and treatment, it is required to introduce the non-invasive diagnostic markers. Long non-coding RNAs (LncRNAs) have higher stability in body fluids in comparison with mRNAs. Therefore, they can be used as efficient non-invasive markers for the early detection of breast cancer (BCa). In the present review we have summarized all of the reported lncRNAs involved in cell cycle regulation in BCa. It has been reported that lncRNAs mainly affect the cell cycle in G1/S transition through the CCND1/CDK4-6 complex. Present review paves the way of introducing the cell cycle related lncRNAs as efficient markers for the early detection of BCa.
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Affiliation(s)
- Amir Sadra Zangouei
- grid.411583.a0000 0001 2198 6209Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ,grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Zangoue
- grid.411701.20000 0004 0417 4622Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran ,grid.411701.20000 0004 0417 4622Department of Anesthesiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Negin Taghehchian
- grid.411583.a0000 0001 2198 6209Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Zangooie
- grid.411701.20000 0004 0417 4622Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran ,grid.411701.20000 0004 0417 4622Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Hamid Reza Rahimi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahya Sadat Alavi
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- grid.411583.a0000 0001 2198 6209Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ,grid.411583.a0000 0001 2198 6209Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro. Eur Arch Otorhinolaryngol 2023; 280:399-408. [PMID: 36001136 PMCID: PMC9813240 DOI: 10.1007/s00405-022-07598-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/04/2022] [Indexed: 01/09/2023]
Abstract
Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.
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Kim DE, Shin SB, Kim CH, Kim YB, Oh HJ, Yim H. PLK1-mediated phosphorylation of β-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC. Theranostics 2023; 13:1198-1216. [PMID: 36793862 PMCID: PMC9925311 DOI: 10.7150/thno.79318] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/21/2023] [Indexed: 02/17/2023] Open
Abstract
Rationale: β-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and β-catenin in NSCLC, their relationship and function in metastatic regulation were investigated. Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and β-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated β-catenin in the EMT of NSCLC. Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-β-induced or active PLK1-driven EMT, β-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. β-catenin is a binding partner of PLK1 in TGF-β-induced EMT and is phosphorylated at S311. Phosphomimetic β-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1. Conclusions: Our findings provide evidence for the critical role of the PLK1/β-catenin/AP-1 axis in metastatic NSCLC, implying that β-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.
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Affiliation(s)
- Da-Eun Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Sol-Bi Shin
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Chang-Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Hyun-Ji Oh
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do 15588, Korea.,Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Korea
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Wang G, Li L, Li Y, Zhang LH. Toosendanin reduces cisplatin resistance in ovarian cancer through modulating the miR-195/ERK/β-catenin pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154571. [PMID: 36610147 DOI: 10.1016/j.phymed.2022.154571] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/27/2022] [Accepted: 11/19/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Cisplatin (DDP) resistance is prevalent in ovarian cancer (OC) patients and contributes to the poor prognosis. Therefore, it is of great significance to develop new agent to intervene and even reverse DDP resistance in OC. Toosendanin (TSN), a triterpenoid extracted from the bark or fruits of Melia toosendan Sieb et Zucc, has been proved to possess significant antitumor activities. However, the efficacy of TSN on DDP resistance in OC has not been reported yet. PURPOSE The aim of this study is to investigate the effects of TSN on DDP resistance in OC and explore the molecular mechanism in vitro and in vivo. METHODS Human OC cell line (SKOV3) and DDP-resistant cell line (SKOV3/DDP) were used. Cell proliferation was measured by CCK-8 and colony formation assay. Annexin V/PI double staining and hoechst 33342 nuclear staining were employed to detect cell apoptosis. Transwell and wound-healing assay were used to determine the invasion and migration potential of cells respectively. Quantitative real-time PCR (qPCR) and western blotting were performed to detect the expression of molecules related to miR-195/ERK/β-catenin pathway. The effects and mechanism of TSN on DDP resistance of OC in vivo was investigated using xenograft model, TUNEL staining assay and immunohistochemistry. RESULTS TSN improved the DDP sensitivity of SKOV3/DDP cells in vitro and in vivo, reflected in promoting inhibition of proliferation, invasion, migration and epithelial mesenchymal transformation (EMT) as well as induction of apoptosis by DDP. TSN could modulate the miR-195/ERK/β-catenin axis by upregulating the miR-195-5p expression and then suppressing ERK/GSK3β/β-catenin pathway which were activated in SKOV3/DDP cells. Moreover, co-treatment of β-catenin pathway activator LiCl or miR-195-5p silencing partially recovered the DDP resistance which was previously repressed by TSN. CONCLUSION Both in vitro and in vivo data demonstrated that TSN could reduce DDP resistance in OC through regulating the miR-195/ERK/β-catenin pathway, highlighting the potential of TSN as an effective agent for favoring overcoming clinical DDP resistance in OC.
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Affiliation(s)
- Ge Wang
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
| | - Lu Li
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yan Li
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Li-Hong Zhang
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Maier T, Stoiber S, Gurnhofer E, Haas M, Kenner L, Heiduschka G, Kadletz-Wanke L, Brkic FF. Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro. Eur Arch Otorhinolaryngol 2023. [PMID: 36001136 DOI: 10.1007/s00405-022-07598-y/figures/4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.
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Affiliation(s)
- Tobias Maier
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria
| | | | - Markus Haas
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria.
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria.
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria.
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria.
| | - Gregor Heiduschka
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kadletz-Wanke
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Faris F Brkic
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
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The FDA-Approved Drug Pyrvinium Selectively Targets ER + Breast Cancer Cells with High INPP4B Expression. Cancers (Basel) 2022; 15:cancers15010135. [PMID: 36612130 PMCID: PMC9817693 DOI: 10.3390/cancers15010135] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/09/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The majority of breast cancers are estrogen receptor-positive (ER+), and endocrine therapies that suppress ER signaling are the standard-of-care treatment for this subset. However, up to half of all ER+ cancers eventually relapse, highlighting a need for improved clinical therapies. The phosphoinositide phosphatase, INPP4B, is overexpressed in almost half of all ER+ breast cancers, and promotes Wnt/β-catenin signaling, cell proliferation and tumor growth. Here, using cell viability assays, we report that INPP4B overexpression does not affect the sensitivity of ER+ breast cancer cells to standard-of-care treatments including the anti-estrogen 4-hydroxytamoxifen (4-OHT) or the PI3Kα inhibitor alpelisib. Examination of four small molecule Wnt inhibitors revealed that ER+ breast cancer cells with INPP4B overexpression were more sensitive to the FDA-approved drug pyrvinium and a 4-OHT-pyrvinium combination treatment. Using 3D culture models, we demonstrated that pyrvinium selectively reduced the size of INPP4B-overexpressing ER+ breast cancer spheroids in the presence and absence of 4-OHT. These findings suggest that repurposing pyrvinium as a Wnt inhibitor may be an effective therapeutic strategy for human ER+ breast cancers with high INPP4B levels.
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Wang Z, Sun L, Liu S, Jiang H. TIPE1 inhibits the growth of Ewing’s sarcoma cells by suppressing Wnt/β-catenin signaling. Clin Transl Oncol 2022; 25:1332-1339. [PMID: 36495466 DOI: 10.1007/s12094-022-03030-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 11/27/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ewing's sarcoma is the second most common bone and soft tissue malignancy in children and adolescents. Tumor necrosis factor-α-induced protein 8-like 1 (TIPE1) functions as a tumor suppressor in several cancers. Activation of Wnt/β-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing's sarcoma. The exact role of TIPE1 in Ewing's sarcoma remains to be elucidated. PURPOSE This study aimed to assess the expression and function of TIPE1 in Ewing's sarcoma. METHODS TIPE1 expression in Ewing's sarcoma cells was determined by qPCR and western blotting. Furthermore, the Ewing's sarcoma cell line RD-ES was transfected with a lentivirus-based TIPE1 expression system to upregulate the expression of TIPE1. The Cell Counting Kit 8 was used to assess the effect of TIPE1 on cell proliferation. The effects of TIPE1 on cell migration and invasion was detected by Transwell assay. Flow cytometry was performed to detect apoptosis. RESULTS Our results suggested lower TIPE1 expression in Ewing's sarcoma cell lines compared with normal osseous cells. TIPE1 remarkably inhibited the growth and proliferation of Ewing's sarcoma cell; TIPE1 also induced apoptosis and inhibited invasion in vitro. TIPE1 inhibited Ewing's sarcoma growth, motility, and survival through regulation of Wnt/β-catenin signaling. CONCLUSIONS Our results demonstrated the anti-tumor function of TIPE1 in Ewing's sarcoma and reveal a novel therapeutic target.
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Landeros N, Gonzalez-Hormazabal P, Pérez-Moreno P, Tapia JC, Jara L. A Single Variant in Pri-miRNA-155 Associated with Susceptibility to Hereditary Breast Cancer Promotes Aggressiveness in Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms232315418. [PMID: 36499743 PMCID: PMC9735695 DOI: 10.3390/ijms232315418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Variants in genes encoding for microRNAs have been associated with their deregulation in breast cancer (BC). Sequencing of microRNAs deregulated in BC was performed using DNA from Chilean patients with a strong family history and negative for mutations in BRCA1/BRCA2. Seventeen variants were identified, three of which were selected for a case-control association study: rs376491654 (miR-335), rs755634302 (miR-497), and rs190708267 (miR-155). For rs190708267 C>T, the heterozygous T allele was detected in four BC cases and absent in controls, while homozygous TT cases were not detected. Variants were modelled in silico, cloned in a plasmid, expressed in BC cell lines, and functional in vitro assays were performed. Overexpression of the miR-155-T allele increased mature miR-155-5p levels in both BC cell lines, suggesting that its presence alters pre-miR-155 processing. Moreover, BC cells overexpressing the miR-155-T allele showed increased proliferation, migration, and resistance to cisplatin-induced death compared to miR-155-C overexpressing cells. Of note, the 3′UTR of APC, GSK3β, and PPP1CA genes, all into the canonical Wnt signaling pathway, were identified as direct targets. APC and GSK3β mRNA levels decreased while PP1 levels increased. These results suggest a pathogenic role of the variant rs190708267 (miR-155) in BRCA 1/2 negative BC, conferring susceptibility and promoting traits of aggressiveness.
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Affiliation(s)
- Natalia Landeros
- Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Patricio Gonzalez-Hormazabal
- Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Pablo Pérez-Moreno
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Julio C Tapia
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Lilian Jara
- Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
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Abdullah MN, Hamid SA, Salhimi SM, Jalil NAS, Al-Amin M, Jumali NS. Design and Synthesis of 1-sec/tert-Butyl-2-Chloro/Nitrophenylbenzimidazole Derivatives: Molecular Docking and In Vitro Evaluation against MDA-MB-231 and MCF-7 Cell Lines. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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40
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ter Steege EJ, Boer M, Timmer NC, Ammerlaan CME, Song J, Derksen PWB, Hilkens J, Bakker ERM. R-spondin-3 is an oncogenic driver of poorly differentiated invasive breast cancer. J Pathol 2022; 258:289-299. [PMID: 36106661 PMCID: PMC9825844 DOI: 10.1002/path.5999] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/28/2022] [Accepted: 08/05/2022] [Indexed: 01/11/2023]
Abstract
R-spondins (RSPOs) are influential signaling molecules that promote the Wnt/β-catenin pathway and self-renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract. Here, we assess the oncogenic capacity of RSPO in breast cancer in a direct fashion by generating and characterizing a novel mouse model with conditional Rspo3 expression in the mammary gland. We also address the prevalence of RSPO gene alterations in breast cancer patients. We found that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number amplifications, which are associated with lack of steroid hormone receptor expression and reduced patient survival. Foremost, we demonstrate the causal oncogenic capacity of RSPO3 in the breast, as conditional Rspo3 overexpression consistently drives the development of mammary adenocarcinomas in our novel Rspo3 breast cancer model. RSPO3-driven mammary tumors typically show poor differentiation, areas of epithelial-to-mesenchymal transition, and metastatic potential. Given the reported interplay in the Wnt/β-catenin pathway, we comparatively analyzed RSPO3-driven mouse mammary tumors versus classical WNT1-driven analogues. This revealed that RSPO3-driven tumors are distinct, as the poorly differentiated tumor morphology and metastatic potential were observed in RSPO3-driven tumorigenesis exclusively, further substantiated by differentiating gene expression profiles. Co-expression of Rspo3 and Wnt1 transduced mammary tumors with a mixed phenotype harboring morphological features characteristic of both transgenes. In summary, we report that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number gains, and these patients have a worse prognosis, whilst providing in vivo evidence that RSPO3 drives poorly differentiated invasive breast cancer in mice. Herewith, we establish RSPO3 as a driver of breast cancer with clinical relevance, proposing RSPO3 as a novel candidate target for therapy in breast cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Eline J ter Steege
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Mandy Boer
- Department of Molecular GeneticsThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Nikki C Timmer
- Department of Molecular GeneticsThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Carola ME Ammerlaan
- Department of Molecular GeneticsThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Ji‐Ying Song
- Department of Experimental Animal PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Patrick WB Derksen
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - John Hilkens
- Department of Molecular GeneticsThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Elvira RM Bakker
- Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands,Department of Molecular GeneticsThe Netherlands Cancer InstituteAmsterdamThe Netherlands
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Lycopene protects against Bisphenol A induced toxicity on the submandibular salivary glands via the upregulation of PPAR-γ and modulation of Wnt/β-catenin signaling. Int Immunopharmacol 2022; 112:109293. [DOI: 10.1016/j.intimp.2022.109293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/20/2022] [Accepted: 09/25/2022] [Indexed: 11/13/2022]
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Proteomics-Based Identification of Dysregulated Proteins in Breast Cancer. Proteomes 2022; 10:proteomes10040035. [PMID: 36278695 PMCID: PMC9590004 DOI: 10.3390/proteomes10040035] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/10/2022] [Accepted: 10/18/2022] [Indexed: 11/18/2022] Open
Abstract
Immunohistochemistry (IHC) is still widely used as a morphology-based assay for in situ analysis of target proteins as specific tumor antigens. However, as a very heterogeneous collection of neoplastic diseases, breast cancer (BC) requires an accurate identification and characterization of larger panels of candidate biomarkers, beyond ER, PR, and HER2 proteins, for diagnosis and personalized treatment, without the limited availability of antibodies that are required to identify specific proteins. Top-down, middle-down, and bottom-up mass spectrometry (MS)-based proteomics approaches complement traditional histopathological tissue analysis to examine expression, modification, and interaction of hundreds to thousands of proteins simultaneously. In this review, we discuss the proteomics-based identification of dysregulated proteins in BC that are essential for the following issues: discovery and validation of new biomarkers by analysis of solid and liquid/non-invasive biopsies, cell lines, organoids and xenograft models; identification of panels of biomarkers for early detection and accurate discrimination between cancer, benign and normal tissues; identification of subtype-specific and stage-specific protein expression profiles in BC grading and measurement of disease progression; characterization of new subtypes of BC; characterization and quantitation of post-translational modifications (PTMs) and aberrant protein-protein interactions (PPI) involved in tumor development; characterization of the global remodeling of BC tissue homeostasis, diagnosis and prognostic information; and deciphering of molecular functions, biological processes and mechanisms through which the dysregulated proteins cause tumor initiation, invasion, and treatment resistance.
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Barzaman K, Vafaei R, Samadi M, Kazemi MH, Hosseinzadeh A, Merikhian P, Moradi-Kalbolandi S, Eisavand MR, Dinvari H, Farahmand L. Anti-cancer therapeutic strategies based on HGF/MET, EpCAM, and tumor-stromal cross talk. Cancer Cell Int 2022; 22:259. [PMID: 35986321 PMCID: PMC9389806 DOI: 10.1186/s12935-022-02658-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 07/19/2022] [Indexed: 02/08/2023] Open
Abstract
As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.
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An improved CUT&RUN method for regulation network reconstruction of low abundance transcription factor. Cell Signal 2022; 96:110361. [DOI: 10.1016/j.cellsig.2022.110361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 11/20/2022]
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Lee MY. Embryonic Programs in Cancer and Metastasis—Insights From the Mammary Gland. Front Cell Dev Biol 2022; 10:938625. [PMID: 35846378 PMCID: PMC9277484 DOI: 10.3389/fcell.2022.938625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/07/2022] [Indexed: 11/24/2022] Open
Abstract
Cancer is characterized as a reversion of a differentiated cell to a primitive cell state that recapitulates, in many aspects, features of embryonic cells. This review explores the current knowledge of developmental mechanisms that are essential for embryonic mouse mammary gland development, with a particular focus on genes and signaling pathway components that are essential for the induction, morphogenesis, and lineage specification of the mammary gland. The roles of these same genes and signaling pathways in mammary gland or breast tumorigenesis and metastasis are then summarized. Strikingly, key embryonic developmental pathways are often reactivated or dysregulated during tumorigenesis and metastasis in processes such as aberrant proliferation, epithelial-to-mesenchymal transition (EMT), and stem cell potency which affects cellular lineage hierarchy. These observations are in line with findings from recent studies using lineage tracing as well as bulk- and single-cell transcriptomics that have uncovered features of embryonic cells in cancer and metastasis through the identification of cell types, cell states and characterisation of their dynamic changes. Given the many overlapping features and similarities of the molecular signatures of normal development and cancer, embryonic molecular signatures could be useful prognostic markers for cancer. In this way, the study of embryonic development will continue to complement the understanding of the mechanisms of cancer and aid in the discovery of novel therapeutic targets and strategies.
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Kadian LK, Arora M, Prasad CP, Pramanik R, Chauhan SS. Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma. Clin Transl Oncol 2022; 24:1014-1032. [PMID: 34990001 DOI: 10.1007/s12094-021-02763-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022]
Abstract
Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.
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Affiliation(s)
- L K Kadian
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - M Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - C P Prasad
- Department of Medical Oncology (Lab), Dr. B. R. Ambedkar-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - R Pramanik
- Department of Medical Oncology, Dr. B. R. Ambedkar-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - S S Chauhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
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Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis. Cell Rep 2022; 39:110851. [PMID: 35649359 DOI: 10.1016/j.celrep.2022.110851] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/25/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022] Open
Abstract
Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and β-catenin to promote the switch of polyubiquitination of β-catenin from K48 to K63, which enhances β-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing β-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated β-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated β-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for β-catenin activation and provide a potential target for tumor prevention and treatment.
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Downstream Signaling of Inflammasome Pathway Affects Patients' Outcome in the Context of Distinct Molecular Breast Cancer Subtypes. Pharmaceuticals (Basel) 2022; 15:ph15060651. [PMID: 35745570 PMCID: PMC9229152 DOI: 10.3390/ph15060651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/20/2022] [Accepted: 05/20/2022] [Indexed: 01/27/2023] Open
Abstract
Inflammasomes are protein complexes involved in the regulation of different biological conditions. Over the past few years, the role of NLRP3 in different tumor types has gained interest. In breast cancer (BC), NLRP3 has been associated with multiple processes including epithelia mesenchymal transition, invasion and metastization. Little is known about molecular modifications of NLRP3 up-regulation. In this study, in a cohort of BCs, the expression levels of NLRP3 and PYCARD were analyzed in combination with CyclinD1 and MYC ones and their gene alterations. We described a correlation between the NLRP3/PYCARD axis and CyclinD1 (p < 0.0001). NLRP3, PYCARD and CyclinD1’s positive expression was observed in estrogen receptor (ER) and progesterone receptor (PgR) positive cases (p < 0.0001). Furthermore, a reduction of NLRP3 and PYCARD expression has been observed in triple negative breast cancers (TNBCs) with respect to the Luminal phenotypes (p = 0.017 and p = 0.0015, respectively). The association NLRP3+/CCND1+ or PYCARD+/CCND1+ was related to more aggressive clinicopathological characteristics and a worse clinical outcome, both for progression free survival (PFS) and overall survival (OS) with respect to NLRP3+/CCND1− or PYCARD+/CCND1− patients, both in the whole cohort and also in the subset of Luminal tumors. In conclusion, our study shows that the NLRP3 inflammasome complex is down-regulated in TNBC compared to the Luminal subgroup. Moreover, the expression levels of NLRP3 and PYCARD together with the alterations of CCND1 results in Luminal subtype BC’ss poor prognosis.
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Abou-Fadel J, Bhalli M, Grajeda B, Zhang J. CmP Signaling Network Leads to Identification of Prognostic Biomarkers for Triple-Negative Breast Cancer in Caucasian Women. Genet Test Mol Biomarkers 2022; 26:198-219. [PMID: 35481969 DOI: 10.1089/gtmb.2021.0221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Triple-negative breast cancer (TNBC) constitutes ∼15% of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target ER, PR, and HER2 receptors are ineffective. Progesterone (PRG) can induce its effects through either classic, nonclassic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or nonclassic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CCM signaling complex (CSC) can couple both nPRs and mPRs into a CmPn signaling network, which plays an important role during nPR(+) breast cancer tumorigenesis. We recently defined the novel CmP signaling network in African American women (AAW)-derived TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Methods: Under mPR-specific steroid actions, we measured alterations to key tumorigenic pathways in Caucasian American women (CAW)- derived TNBC cells, with RNAseq/proteomic and systems biology approaches. Exemption from ethics approval from IRB: This study only utilized cultured NBC cell lines with publicly available TNBC clinical data sets. Results: Our results demonstrated that TNBCs in CAW share similar altered signaling pathways, as TNBCs in AAW, under mPR-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have deconvoluted the CmP signalosome, using systems biology approaches and CAW-TNBC clinical data, to identify 21 new CAW-TNBC-specific prognostic biomarkers that reinforce the definitive role of CSC and mPR signaling during CAW-TNBC tumorigenesis. Conclusion: This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.
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Affiliation(s)
- Johnathan Abou-Fadel
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
| | - Muaz Bhalli
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
| | - Brian Grajeda
- Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA
| | - Jun Zhang
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
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Tanton H, Sewastianik T, Seo HS, Remillard D, Pierre RS, Bala P, Aitymbayev D, Dennis P, Adler K, Geffken E, Yeoh Z, Vangos N, Garbicz F, Scott D, Sethi N, Bradner J, Dhe-Paganon S, Carrasco RD. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer. SCIENCE ADVANCES 2022; 8:eabm3108. [PMID: 35486727 PMCID: PMC9054024 DOI: 10.1126/sciadv.abm3108] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.
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Affiliation(s)
- Helen Tanton
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tomasz Sewastianik
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine,, Warsaw, Poland
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - David Remillard
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Roodolph St. Pierre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Peter Dennis
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Keith Adler
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ezekiel Geffken
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Zoe Yeoh
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nicholas Vangos
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Filip Garbicz
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine,, Warsaw, Poland
| | - David Scott
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nilay Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - James Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Ruben D. Carrasco
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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