scholarly journals Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

2020 ◽  
Vol 21 (2) ◽  
pp. 661 ◽  
Author(s):  
Celeste Caruso Bavisotto ◽  
Antonella Marino Gammazza ◽  
Filippa Lo Cascio ◽  
Emanuele Mocciaro ◽  
Alessandra Maria Vitale ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Culture Media ◽  
Neuroblastoma Cell ◽  
Cancer Development ◽  
Protective Mechanism ◽  
Protein Homeostasis ◽  
Matrix Remodeling ◽  
Dependent Manner ◽  
Mesenchymal Transition

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.

scholarly journals Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinfen Wei ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Ziqing He ◽  
Dawei Jiang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Matrix Remodeling ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Associated Macrophage ◽  
Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

scholarly journals MicroRNA-381—A Key Transcriptional Regulator: Its Biological Function and Clinical Application Prospects in Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Xue Zeng ◽  
Zhe Cao ◽  
Wenhao Luo ◽  
Lianfang Zheng ◽  
Taiping Zhang
Keyword(s):  
Prognostic Factor ◽  
Clinical Application ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Stage ◽  
Cancer Development ◽  
Messenger Rnas ◽  
Mesenchymal Transition ◽  
Oncogenic Pathways ◽  
Application Prospects

MicroRNAs (miRNAs) are small non-coding RNA molecules that function by regulating messenger RNAs. Recent studies have shown that miRNAs play important roles in multiple processes of cancer development. MiR-381 is one of the most important miRNAs in cancer progression. MiR-381 is downregulated in some cancers and upregulated in other cancers, including glioma, epithelial sarcoma, and osteosarcoma. MiR-381 regulates epithelial–mesenchymal transition (EMT), chemotherapeutic resistance, radioresistance, and immune responses. Thus, miR-381 participates in tumor initiation, progression, and metastasis. Moreover, miR-381 functions in various oncogenic pathways, including the Wnt/β-catenin, AKT, and p53 pathways. Clinical studies have shown that miR-381 could be considered a biomarker or a novel prognostic factor. Here, we summarize the present studies on the role of miR-381 in cancer development, including its biogenesis and various affected signaling pathways, and its clinical application prospects. MiR-381 expression is associated with tumor stage and survival time, making miR-381 a novel prognostic factor.

scholarly journals RNF20 Is Critical for Snail-Mediated E-Cadherin Repression in Human Breast Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Danping Wang ◽  
Yifan Wang ◽  
Xuebiao Wu ◽  
Xiangxing Kong ◽  
Jun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Colony Formation ◽  
Human Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Dependent Manner ◽  
Human Breast ◽  
Mesenchymal Transition ◽  
E Cadherin

BackgroundE-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often repressed due to Snail-mediated epigenetic modification; however, the exact mechanism remains unclear. There is an urgent need to understand the determinants of tumor aggressiveness and identify potential therapeutic targets in breast cancer.Experimental designWe studied the association of RNF20 with Snail and G9a by co-immunoprecipitation. We employed quantitative real-time PCR, ChIP, transwell assay, colony formation assay, and mammosphere assay to dissect the molecular events associated with the repression of E-cadherin in human breast cancer. We used a proteogenomic dataset that contains 105 breast tumor samples to determine the clinical relevance of RNF20 by Kaplan-Meier analyses.ResultsIn this study, we identified that Snail interacted with RNF20, an E3 ubiquitin-protein ligase responsible for monoubiquitination of H2BK120, and G9a, a methyltransferase for H3K9me2. RNF20 expression led to the inhibition of E-cadherin expression in the human breast cancer cells. Mechanically, we showed that RNF20 and H3K9m2 were enriched on the promoter of E-cadherin and knockdown of Snail reduced the enrichment of RNF20, showing a Snail-dependent manner. RNF20 expression enhanced breast cancer cell migration, invasion, tumorsphere and colony formation. Clinically, patients with high RNF20 expression had shorter overall survival.ConclusionRNF20 expression contributes to EMT induction and breast cancer progression through Snail-mediated epigenetic suppression of E-cadherin expression, suggesting the importance of RNF20 in breast cancer.

scholarly journals Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Archana Katoch ◽  
Debasis Nayak ◽  
Mir Mohd. Faheem ◽  
Aviral Kumar ◽  
Promod Kumar Sahu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Checkpoint Kinase ◽  
Mesenchymal Transition ◽  
Checkpoint Kinase 2 ◽  
Clinical Benefits ◽  
Colorectal Cancer Progression

AbstractEpithelial–mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal cancer (CRC) cells transiently exposed to 5-fluorouracil (5-FU) (a chemotherapeutic drug for CRC) as well as 5-FU-resistant cells (5-FU-R) develop EMT characters as evidenced by activation of Vimentin and augmented invasive properties. On the other hand, 4DPG (4′-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates EMT and invadopodia formation abilities of HCT-116/5-FU-R and SW-620/5-FU-R cells. Treatment with 4DPG restrains Vimentin phosphorylation (Ser38) in 5-FU-R cells, along with downregulation of mesenchymal markers Twist1 and MMP-2 while augmenting the expression of epithelial markers E-cadherin and TIMP-1. Moreover, 4DPG boosts the tumor-suppressor protein, checkpoint kinase 2 (Chk2) via phosphorylation at Thr68 in a dose-dependent manner in 5-FU-R cells. Mechanistically, SiRNA-mediated silencing of Chk2, as well as treatment with Chk2-specific small-molecule inhibitor (PV1019), divulges that 4DPG represses Vimentin activation in a Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled that 4DPG prevents complex formation between Vimentin and p53 resulting in the rescue of p53 and its nuclear localization in aggressive 5-FU-R cells. In addition, 4DPG confers suitable pharmacokinetic properties and strongly abrogates tumor growth, polyps formation, and lung metastasis in an orthotopic rat colorectal carcinoma model. In conclusion, our findings demonstrate 4DPG as a targeted antitumor/anti-metastatic pharmacological lead compound to circumvent EMT-associated drug resistance and suggest its clinical benefits for the treatment of aggressive cancers.

scholarly journals PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

2018 ◽  
Vol 51 (5) ◽  
pp. 2434-2444 ◽  
Author(s):  
Deyuan Fu ◽  
Chunlan He ◽  
Jinli Wei ◽  
Zhengquan Zhang ◽  
Yulin Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Target Therapy ◽  
Enzymatic Reaction ◽  
Disease Free Survival ◽  
Transition Process ◽  
Dependent Manner ◽  
Poor Overall Survival ◽  
Mesenchymal Transition

Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer.

scholarly journals Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions

2018 ◽  
Vol 19 (9) ◽  
pp. 2787 ◽  
Author(s):  
Takeshi Tsuda
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Structural Integrity ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Elastic Fibers ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Pathological Conditions

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial–mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases.

scholarly journals Is There an Interconnection between Epithelial–Mesenchymal Transition (EMT) and Telomere Shortening in Aging?

2021 ◽  
Vol 22 (8) ◽  
pp. 3888
Author(s):  
Siti A. M. Imran ◽  
Muhammad Dain Yazid ◽  
Ruszymah Bt Hj Idrus ◽  
Manira Maarof ◽  
Abid Nordin ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cell Biology ◽  
Epithelial Mesenchymal Transition ◽  
Primitive Streak ◽  
Vital Role ◽  
Potential Interaction ◽  
Cancer Development ◽  
Mesenchymal Transition ◽  
Age Related ◽  
Type 3

Epithelial–Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.

scholarly journals USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Yueguang Wu ◽  
Yingqiu Zhang ◽  
Duchuang Wang ◽  
Yang Zhang ◽  
Jinrui Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
E3 Ligases ◽  
Tumor Dissemination

Abstract Chemotherapy remains an essential part of diverse treatment regimens against human malignancies. However, recent progressions have revealed a paradoxical role of chemotherapies to induce the cancer stem cell-like features that facilitate chemoresistance and tumor dissemination, with the underlying mechanisms underinvestigated. The zinc-finger transcription factor Snail1 is a central regulator during the epithelial-mesenchymal transition process and is closely implicated in cancer progression. Snail1 expression is strictly regulated at multiple layers, with its stability governed by post-translational ubiquitylation that is counterbalanced by the activities of diverse E3 ligases and deubiquitylases. Here we identify the deubiquitylase USP29 as a novel stabilizer of Snail1, which potently restricts its ubiquitylation in a catalytic activity-dependent manner. Bioinformatic analysis reveals a reverse correlation between USP29 expression and prognosis in lung adenocarcinoma patients. USP29 is unique among Snail1 deubiquitylases through exhibiting chemotherapy-induced upregulation. Mechanistically, oxidative stresses incurred by chemotherapy stimulate transcriptional activation of USP29. USP29 upregulation enhances the cancer stem cell-like characteristics in lung adenocarcinoma cells to promote tumorigenesis in athymic nude mice. Our findings uncover a novel mechanism by which chemotherapy induces cancer stemness and suggest USP29 as a potential therapeutic target to impede the development of chemoresistance and metastasis in lung adenocarcinoma.

scholarly journals EMT changes actin cortex rheology in a cell-cycle dependent manner

2020 ◽  
Author(s):  
Kamran Hosseini ◽  
Annika Frenzel ◽  
Elisabeth Fischer-Friedrich
Keyword(s):  
Cancer Progression ◽  
Structural Changes ◽  
Epithelial Mesenchymal Transition ◽  
Cellular Transformation ◽  
Metastatic Potential ◽  
Cellular Migration ◽  
Characteristic Time Scale ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Actin Cortex

The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, cancer cells were shown to change their mechanical properties based on different degrees of malignancy and metastatic potential. Epithelial-Mesenchymal transition (EMT) is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the frequency-dependent viscoelastic mechanics of the actin cortex is still lacking. In this work, we have used an established AFM-based method of cell confinement to quantify the rheology of the actin cortex of human breast, lung and prostate epithelial cells before and after EMT in a frequency range of 0.02 − 2 Hz. Interestingly, we find for all cell lines opposite EMT-induced changes in interphase and mitosis; while the actin cortex softens upon EMT in interphase, it stiffens in mitosis. Our rheological data can be accounted for by a rheological model with a characteristic time scale of slowest relaxation. In conclusion, our study discloses a consistent rheological trend induced by EMT in human cells of diverse tissue origin reflecting major structural changes of the actin cytoskeleton upon EMT.

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