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Zheng J, Du Y, Shao W, Li J, Zhao P, Zhang Q. Effective-compounds of Jinshui Huanxian Formula acts as an SRC inhibitor to inhibit HK2-mediated H3K18 lactation and improve pulmonary fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156628. [PMID: 40090047 DOI: 10.1016/j.phymed.2025.156628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 03/01/2025] [Accepted: 03/06/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND The Active Ingredient Composition of Jinshui Huanxian Formula (ECC-JHF) consists of five active ingredients: icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, which demonstrate notable therapeutic effects on pulmonary fibrosis. PURPOSE Inhibition of glycolysis has been demonstrated to be effective in treating experimental idiopathic pulmonary fibrosis (IPF). This research seeks to explore the impact of aerobic glycolysis on the mitigation of pulmonary fibrosis through ECC-JHF. METHODS A pulmonary fibrosis mouse model was generated through the administration of bleomycin (Bleomycin). The degree of pulmonary fibrosis was analyzed through hematoxylin and eosin (H&E) staining as well as Masson's trichrome staining. Western Blot (WB), Immunofluorescence (IF), and real-time quantitative PCR (Q-PCR) assay for fibroblast activation markers and glycolysis-related genes in lung tissues. The Lactic Acid (LA) Content Assay Kit was employed to quantify lactate concentrations in lung tissues and fibroblast cultures. Immunoprecipitation (IP) was applied to detect lactylated modified protein levels, and mass spectrometry (MS) was used to analyze lactate substrate profiles in fibroblasts. WB was employed to detect the lactate modification level of histone H3K18 (H3K18la). The targets of ECC-JHF were analyzed using network pharmacology, while molecular docking and cellular enthusiasm transfer analysis (CETSA) examined the binding of ECC-JHF to SRC. The influence of ECC-JHF on SRC activation was assessed using WB. SRC small interfering RNA (siSRC) was designed and transfected into L929 cells to validate the function of SRC in the inhibition of fibroblast activation by ECC-JHF. RESULTS In BLM-induced pulmonary fibrosis mice, ECC-JHF significantly reduced alveolar inflammation and collagen deposition. In lung tissues and fibroblasts, ECC-JHF notably inhibited the expression of HK2, lactate levels, and lactylated modifying proteins. IP-MS and WB analyses showed that ECC-JHF significantly reduced H3K18la levels. Network pharmacology analysis, molecular docking and CETSA results indicated that SRC serves as a key target for ECC-JHF. siSRC effectively mitigated the impact of ECC-JHF on the expression of HK2, levels of H3K18la, and the activation of fibroblasts. CONCLUSION ECC-JHF may improve pulmonary fibrosis by inhibiting SRC activation, blocking HK2-mediated lactate production, down-regulating H3K18la levels, and inhibiting fibroblast activation. Our results serve as a significant reference for the advancement of ECC-JHF and the exploration of IPF.
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Affiliation(s)
- Jiaping Zheng
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China
| | - Yan Du
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Wenbo Shao
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China
| | - Jiansheng Li
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China; Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Peng Zhao
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Qin Zhang
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R. China, Zhengzhou, Henan 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China.
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Raji L, Tetteh A, Amin ARMR. Role of c-Src in Carcinogenesis and Drug Resistance. Cancers (Basel) 2023; 16:32. [PMID: 38201459 PMCID: PMC10778207 DOI: 10.3390/cancers16010032] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The aberrant transformation of normal cells into cancer cells, known as carcinogenesis, is a complex process involving numerous genetic and molecular alterations in response to innate and environmental stimuli. The Src family kinases (SFK) are key components of signaling pathways implicated in carcinogenesis, with c-Src and its oncogenic counterpart v-Src often playing a significant role. The discovery of c-Src represents a compelling narrative highlighting groundbreaking discoveries and valuable insights into the molecular mechanisms underlying carcinogenesis. Upon oncogenic activation, c-Src activates multiple downstream signaling pathways, including the PI3K-AKT pathway, the Ras-MAPK pathway, the JAK-STAT3 pathway, and the FAK/Paxillin pathway, which are important for cell proliferation, survival, migration, invasion, metastasis, and drug resistance. In this review, we delve into the discovery of c-Src and v-Src, the structure of c-Src, and the molecular mechanisms that activate c-Src. We also focus on the various signaling pathways that c-Src employs to promote oncogenesis and resistance to chemotherapy drugs as well as molecularly targeted agents.
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Affiliation(s)
| | | | - A. R. M. Ruhul Amin
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV 25755, USA; (L.R.); (A.T.)
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Antmen E, Ermis M, Kuren O, Beksac K, Irkkan C, Hasirci V. Nuclear Deformability of Breast Cells Analyzed from Patients with Malignant and Benign Breast Diseases. ACS Biomater Sci Eng 2023; 9:1629-1643. [PMID: 36706038 DOI: 10.1021/acsbiomaterials.2c01059] [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: 01/28/2023]
Abstract
Breast cancer is a heterogeneous and dynamic disease, in which cancer cells are highly responsive to alterations in the microenvironment. Today, conventional methods of detecting cancer give a rather static image of the condition of the disease, so dynamic properties such as invasiveness and metastasis are difficult to capture. In this study, conventional molecular-level evaluations of the patients with breast adenocarcinoma were combined with in vitro methods on micropatterned poly(methyl methacrylate) (PMMA) biomaterial surfaces that deform cells. A correlation between deformability of the nuclei and cancer stemness, invasiveness, and metastasis was sought. Clinical patient samples were from regions of the breast with different proximities to the tumor. Responses at the single-cell level toward the micropatterned surfaces were studied using CD44/24, epithelial cell adhesion marker (EpCAM), MUC1, and PCK. Results showed that molecular markers and shape descriptors can discriminate the cells from different proximities to the tumor center and from different patients. The cells with the most metastatic and invasive properties showed both the highest deformability and the highest level of metastatic markers. In conclusion, by using a combination of molecular markers together with nuclear deformation, it is possible to improve detection and separation of subpopulations in heterogenous breast cancer specimens at the single-cell level.
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Affiliation(s)
- Ezgi Antmen
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Menekse Ermis
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Ozgur Kuren
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Kemal Beksac
- Department of General Surgery, Ankara Oncology Hospital, Yenimahalle, Ankara06800, Turkey
| | - Cigdem Irkkan
- Department of Pathology, Ankara Oncology Hospital, Yenimahalle, Ankara06800, Turkey
| | - Vasif Hasirci
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
- Department of Biomedical Engineering, Acibadem Mehmet Ali Aydinlar University (ACU), Istanbul34752, Turkey
- ACU Biomaterials Center, Acibadem Mehmet Ali Aydinlar University (ACU), Atasehir, Istanbul34752, Turkey
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Marni R, Malla M, Chakraborty A, Malla R. Proteomic profiling and ROC analysis identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug in resistant TNBC. Life Sci 2023; 320:121534. [PMID: 36889667 DOI: 10.1016/j.lfs.2023.121534] [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: 12/12/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 03/08/2023]
Abstract
Triple-negative breast cancer is high heterogeneous, aggressive, and metastatic with poor prognosis. Despite of advances in targeted therapies, TNBC has been reported to cause high morbidity and mortality. A rare subpopulation within the tumor microenvironment organized into a hierarchy of cancer stem cells is responsible for therapy resistance and tumor recurrence. Repurposing of antiviral drugs for cancer treatment is gaining momentum due to reduced cost, labour, and research time, but limited due to lack of prognostic, and predictive markers. The present study investigates proteomic profiling and ROC analysis to identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug 2-thio-6-azauridine (TAU) in resistant TNBC. The stemness of MDA-MB 231 and MDA-MD 468 adherent cells was enriched by culturing them under non-adherent and non-differentiation conditions. Then, CD151+ subpopulation was isolated and characterized for the enrichment of stemness. This study found that CD151 has overexpressed in stemness enriched subpopulations, and also showed CD44 high and CD24 low expression along with stem cell-related transcription factors octamer-binding transcription factor 4 (OCT4) and Sex determining Y-box 2 (SOX2). This study also found that TAU induced significant cytotoxicity and genotoxicity in the CD151+TNBC subpopulation and inhibited their proliferation by inducing DNA damage, cell cycle arrest at the G2M phase, and apoptosis. Further, a proteomic profiling study showed that the expression of CD151 along with ELAVL1, an RNA-binding protein, was significantly reduced with TAU treatment. KM plotter showed correlation of CD151 and ELAVL1 gene expression with a poor prognosis of TNBC. ROC analysis predicted and validated CD151 and ELAVL1 as best therapy response marker for TAU in TNBC. These findings provide new insight into repurposing antiviral drug TAU for treatment of metastatic and drug resistant TNBC.
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Affiliation(s)
- Rakshmitha Marni
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, A.P., India
| | - Manas Malla
- Department of Computer Science and Engineering, GITAM School of Technology, GITAM (Deemed to be University), Visakhapatnam 530045, A.P., India
| | | | - RamaRao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, A.P., India.
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Pelaz SG, Tabernero A. Src: coordinating metabolism in cancer. Oncogene 2022; 41:4917-4928. [PMID: 36217026 PMCID: PMC9630107 DOI: 10.1038/s41388-022-02487-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/08/2022]
Abstract
Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.
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Affiliation(s)
- Sara G Pelaz
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
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6
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Shao W, Liu L, Zheng F, Ma Y, Zhang J. The potent role of Src kinase-regulating glucose metabolism in cancer. Biochem Pharmacol 2022; 206:115333. [PMID: 36404485 DOI: 10.1016/j.bcp.2022.115333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/02/2022]
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Jones JC, Bodenstine TM. Connexins and Glucose Metabolism in Cancer. Int J Mol Sci 2022; 23:ijms231710172. [PMID: 36077565 PMCID: PMC9455984 DOI: 10.3390/ijms231710172] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.
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8
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Lasagna M, Ventura C, Hielpos MS, Mardirosian MN, Martín G, Miret N, Randi A, Núñez M, Cocca C. Endocrine disruptor chlorpyrifos promotes migration, invasion, and stemness phenotype in 3D cultures of breast cancer cells and induces a wide range of pathways involved in cancer progression. ENVIRONMENTAL RESEARCH 2022; 204:111989. [PMID: 34506784 DOI: 10.1016/j.envres.2021.111989] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 06/13/2023]
Abstract
Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitate hormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2D cultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition in MCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposing factor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 μM CPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC. Furthermore, 0.05 μM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion using both Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. In turn, 50 μM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPF increased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05 μM boosted p-AKT, p-GSK-3β and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3β was dependent on ERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38 induced by 50 μM CPF was dependent on the c-SRC pathway. We also observed that 0.05 μM CPF increased IGF-1R and IRS-1 expression and that 50 μM CPF induced IGF-1Rβ phosphorylation. In the MDA-MB-231 cell line, 0.05 and 50 μM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3β were also induced by CPF at 0.05 and 50 μM, and an increase in p-P38 was observed at 50 μM. Taken together, these data provide support for the notion that CPF may represent a risk factor for breast cancer development and progression.
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Affiliation(s)
- M Lasagna
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - C Ventura
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Universidad Nacional de La Plata-CONICET, Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), La Plata, Argentina
| | - M S Hielpos
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - M N Mardirosian
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - G Martín
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - N Miret
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Buenos Aires, Argentina
| | - A Randi
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Buenos Aires, Argentina
| | - M Núñez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - C Cocca
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
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Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy. Cells 2021; 10:cells10123348. [PMID: 34943856 PMCID: PMC8699513 DOI: 10.3390/cells10123348] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduce expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This can lead to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.
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Mayoral-Varo V, Sánchez-Bailón MP, Calcabrini A, García-Hernández M, Frezza V, Martín ME, González VM, Martín-Pérez J. The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells. Cancers (Basel) 2021; 13:462. [PMID: 33530373 PMCID: PMC7865352 DOI: 10.3390/cancers13030462] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 02/05/2023] Open
Abstract
The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.
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Affiliation(s)
- Víctor Mayoral-Varo
- Instituto de Investigaciones Biomédicas A, Sols/Dpto. Bioquímica (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.M.-V.); (M.P.S.-B.); (A.C.)
| | - María Pilar Sánchez-Bailón
- Instituto de Investigaciones Biomédicas A, Sols/Dpto. Bioquímica (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.M.-V.); (M.P.S.-B.); (A.C.)
- Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Annarica Calcabrini
- Instituto de Investigaciones Biomédicas A, Sols/Dpto. Bioquímica (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.M.-V.); (M.P.S.-B.); (A.C.)
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
| | - Marta García-Hernández
- Grupo de Aptámeros, Servicio Bioquímica-Investigación, IRYCIS-Hospital Ramón y Cajal. Ctra. Colmenar Viejo km 9100, 28034 Madrid, Spain; (M.G.-H.); (V.F.); (M.E.M.); (V.M.G.)
| | - Valerio Frezza
- Grupo de Aptámeros, Servicio Bioquímica-Investigación, IRYCIS-Hospital Ramón y Cajal. Ctra. Colmenar Viejo km 9100, 28034 Madrid, Spain; (M.G.-H.); (V.F.); (M.E.M.); (V.M.G.)
| | - María Elena Martín
- Grupo de Aptámeros, Servicio Bioquímica-Investigación, IRYCIS-Hospital Ramón y Cajal. Ctra. Colmenar Viejo km 9100, 28034 Madrid, Spain; (M.G.-H.); (V.F.); (M.E.M.); (V.M.G.)
| | - Víctor M. González
- Grupo de Aptámeros, Servicio Bioquímica-Investigación, IRYCIS-Hospital Ramón y Cajal. Ctra. Colmenar Viejo km 9100, 28034 Madrid, Spain; (M.G.-H.); (V.F.); (M.E.M.); (V.M.G.)
| | - Jorge Martín-Pérez
- Instituto de Investigaciones Biomédicas A, Sols/Dpto. Bioquímica (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.M.-V.); (M.P.S.-B.); (A.C.)
- Instituto de Investigaciones Sanitarias del Hospital La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain
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Gao X, Dong QZ. Advance in metabolism and target therapy in breast cancer stem cells. World J Stem Cells 2020; 12:1295-1306. [PMID: 33312399 PMCID: PMC7705469 DOI: 10.4252/wjsc.v12.i11.1295] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/06/2020] [Accepted: 09/27/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.
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Affiliation(s)
- Xu Gao
- Department of Breast Surgery, Yiwu Maternity and Children Hospital, Yiwu 322000, Zhejiang Province, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai 200032, China
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Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells. Int J Mol Sci 2020; 21:ijms21207437. [PMID: 33050159 PMCID: PMC7588004 DOI: 10.3390/ijms21207437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/03/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.
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