scholarly journals Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 555
Author(s):  
Soyoung Hur ◽  
Eungyeong Jang ◽  
Jang-Hoon Lee
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

scholarly journals The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 130067 ◽  
Author(s):  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Phosphorylation ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

scholarly journals MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Lorenzo Stramucci ◽  
Angelina Pranteda ◽  
Arianna Stravato ◽  
Carla Azzurra Amoreo ◽  
Annarita Pennetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Map Kinases ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Mapk Pathway ◽  
Primary Cultures ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and understanding its underlying molecular mechanisms is crucial for the development of therapeutic strategies. The mitogen-activated protein kinase-kinase 3 (MKK3) is a specific activator of p38 MAP kinases (p38 MAPKs), which contributes to the regulation of several cellular functions, such as proliferation, differentiation, apoptosis as well as response to drugs. At present, the exact MKK3/p38 MAPK pathway contribution in cancer is heavily debated because of its pleiotropic function. In this work, we retrospectively explored the prognostic and pathobiologic relevance of MKK3 in a cohort of CRC patients and assessed MKK3 molecular functions in a panel of CRC lines and colonocytes primary cultures. We found increased MKK3 levels in late-stage CRC patients which correlated with shorter overall survival. Herein, we report that the MKK3 targeting by inducible RNA interference univocally exerts antitumor effects in CRC lines but not in primary colonocytes. While MKK3 depletion per se affects growth and survival by induction of sustained autophagy and death in some CRC lines, it potentiates response to chemotherapeutic drug 5-fluorouracil (5-FU) in all of the tested CRC lines in vitro. Here, we demonstrate for the first time that in CRC the MKK3 specifically activates p38delta MAPK isoform to sustain prosurvival signaling and that such effect is exacerbated upon 5-FU challenge. Indeed, p38delta MAPK silencing recapitulates MKK3 depletion effects in CRC cells in vitro and in vivo. Overall, our data identified a molecular mechanism through which MKK3 supports proliferation and survival signaling in CRC, further supporting MKK3 as a novel and extremely attractive therapeutic target for the development of promising strategies for the management of CRC patients.

scholarly journals Targeting the Epithelial-to-Mesenchymal Transition in Cancer Stem Cells for a Better Clinical Outcome of Glioma

2020 ◽  
Vol 19 ◽  
pp. 153303382094805
Author(s):  
Yu-bao Lu ◽  
Tian-Jiao Sun ◽  
Yu-tong Chen ◽  
Zong-Yan Cai ◽  
Jia-Yu Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Tumor Therapy ◽  
Tumor Development ◽  
Mesenchymal Transition ◽  
Important Target ◽  
The Central Nervous System

Glioma is one of the most common malignant tumors of the central nervous system with a poor prognosis at present due to lack of effective treatment options. Its initiation, migration, and multipotency are affected by cancer stem cell’s transition. Previous studies imply that changes in the cancer stem cells can affect the malignant differentiation of the tumor. We found that the epithelial-to-mesenchymal transition (EMT)-related regulatory pathway is an important target for tumor therapy. In this review, we discuss the transition factor of EMT and 3 specific pathways that affect the EMT of cancer stem cells during tumor development. We conclude that targeting the EMT process of cancer stem cells can be a feasible approach in the treatment of glioma.

scholarly journals LncRNA LL22NC03-N14H11.1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Tingzhuang Yi ◽  
Hongcheng Luo ◽  
Fengxue Qin ◽  
Qi Jiang ◽  
Shougao He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Epithelial To Mesenchymal Transition ◽  
Mapk Pathway ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Potential Biomarker

Abstract Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.

The Chemosensitizing Role of Metformin in Anticancer Therapy

2020 ◽  
Vol 20 ◽  
Author(s):  
Zhimin Tang ◽  
Nan Tang ◽  
Shanshan Jiang ◽  
Yangjinming Bai ◽  
Chenxi Guan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Anticancer Therapy ◽  
Mapk Signaling ◽  
Chemotherapeutic Drugs ◽  
Mesenchymal Transition ◽  
Anticancer Effects ◽  
Selective Targeting ◽  
Cancer Types

: Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anticancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anticancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of cancer stem cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse epithelial to mesenchymal transition (EMT) and multidrug resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1α, and mitogenactivated protein kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and pyruvate kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.

scholarly journals Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 183
Author(s):  
Akshita B. Bhatt ◽  
Saloni Patel ◽  
Margarite D. Matossian ◽  
Deniz A. Ucar ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

scholarly journals Targeting AGTR1/NF-κB /CXCR4 axis by miR-155 attenuates oncogenesis in Glioblastoma

2019 ◽  
Author(s):  
Anukriti Singh ◽  
Nidhi Srivastava ◽  
Bushra Ateeq
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Tumor Burden ◽  
Luciferase Reporter ◽  
Angiotensin Ii Receptor ◽  
Mesenchymal Transition ◽  
Immunodeficient Mice ◽  
Cxcr4 Signaling ◽  
Iκb Kinase

AbstractGlioblastoma (GBM) represents the most aggressive malignancy of the brain. Angiotensin II Receptor Type 1 (AGTR1) upregulation has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3’untranslated region (3’UTR) of AGTR1 by using prediction algorithms for binding of miRNA. Interestingly, miR-155 showed conserved binding on the 3’UTR of AGTR1, subsequently confirmed by AGTR1-3’UTR-luciferase reporter assay. Furthermore, stable miR-155 overexpressing GBM cells show decrease in AGTR1-mediated cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show remarkable reduction (∼95%) in tumor burden compared to control. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 and AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated, angiogenesis, epithelial-to-mesenchymal transition, stemness, ERK/MAPK signaling and promotes apoptosis. Similar effects in cell-based assays were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies.

scholarly journals Molecular regulation of Snai2 in development and disease

2019 ◽  
Vol 132 (23) ◽  
Author(s):  
Wenhui Zhou ◽  
Kayla M. Gross ◽  
Charlotte Kuperwasser
Keyword(s):  
Transcription Factor ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Zinc Finger Protein ◽  
Main Role ◽  
Biological Processes ◽  
Developmental Defects ◽  
Mesenchymal Transition ◽  
Damage Repair

ABSTRACT The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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