FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis

Abstract Background There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. Methods Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice. Results The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527. Conclusions Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

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The role of exosomes in lung cancer metastasis and clinical applications: an updated review

Journal of Translational Medicine ◽

10.1186/s12967-021-02985-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lei Yin ◽

Xiaotian Liu ◽

Xuejun Shao ◽

Tao Feng ◽

Jun Xu ◽

...

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Cancer Cell ◽

Cancer Metastasis ◽

Value Assessment ◽

Lung Carcinogenesis ◽

Research Attention ◽

Mesenchymal Transition ◽

Lung Cancer Metastasis

AbstractLung cancer is the leading cause of cancer-associated deaths accounting for 24% of all cancer deaths. As a crucial phase of tumor progression, lung cancer metastasis is linked to over 70% of these mortalities. In recent years, exosomes have received increasing research attention in their role in the induction of carcinogenesis and metastasis in the lung. In this review, recent studies on the contribution of exosomes to lung cancer metastasis are discussed, particularly highlighting the role of lung tumor-derived exosomes in immune system evasion, epithelial-mesenchymal transition, and angiogenesis, and their involvement at both the pre-metastatic and metastatic phases. The clinical application of exosomes as therapeutic drug carriers, their role in antitumor drug resistance, and their utility as predictive biomarkers in diagnosis and prognosis are also presented. The metastatic activity, a complex multistep process of cancer cell invasion, survival in blood vessels, attachment and subsequent colonization of the host's organs, is integrated with exosomal effects. Exosomes act as functional mediating factors in cell–cell communication, influencing various steps of the metastatic cascade. To this end, lung cancer cell-derived exosomes enhance cell proliferation, angiogenesis, and metastasis, regulate drug resistance, and antitumor immune activities during lung carcinogenesis, and are currently being explored as an important component in liquid biopsy assessment for diagnosing lung cancer. These nano-sized extracellular vesicles are also being explored as delivery vehicles for therapeutic molecules owing to their unique properties of biocompatibility, circulatory stability, decreased toxicity, and tumor specificity. The current knowledge of the role of exosomes highlights an array of exosome-dependent pathways and cargoes that are ripe for exploiting therapeutic targets to treat lung cancer metastasis, and for predictive value assessment in diagnosis, prognosis, and anti-tumor drug resistance.

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Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain

Clinical & Experimental Metastasis ◽

10.1007/s10585-008-9210-2 ◽

2008 ◽

Vol 27 (2) ◽

pp. 97-105 ◽

Cited By ~ 74

Author(s):

Cimona V. Hinton ◽

Shalom Avraham ◽

Hava Karsenty Avraham

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Signaling Axis ◽

The Brain

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Metabolism is not a Major Contributor to the Toxicity of Piperaquine, a Major Partner Antimalarial in Artemisinin-Based Combination Therapy

Current Drug Metabolism ◽

10.2174/1389200222666210928124943 ◽

2021 ◽

Vol 22 ◽

Author(s):

Liyuan Zhang ◽

Zhaohua Liu ◽

Yunrui Zhang ◽

Yuewu Xie ◽

Jie Xing

Keyword(s):

Histopathological Examination ◽

High Dose ◽

Mrna Levels ◽

Apoptosis Pathway ◽

Hepatocellular Damage ◽

Serum Biochemical ◽

Oral Doses ◽

Dose Dependent ◽

Cumulative Exposures

Background: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. Objectives: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. Method: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. Results: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. Conclusions: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.

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A Role of Tumor-Released Exosomes in Paracrine Dissemination and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms19123968 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3968 ◽

Cited By ~ 17

Author(s):

Enrico Spugnini ◽

Mariantonia Logozzi ◽

Rossella Di Raimo ◽

Davide Mizzoni ◽

Stefano Fais

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

The Body ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Target Organs

Metastatic diffusion is thought to be a multi-step phenomenon involving the release of cells from the primary tumor and their diffusion through the body. Currently, several hypotheses have been put forward in order to explain the origin of cancer metastasis, including epithelial–mesenchymal transition, mutagenesis of stem cells, and a facilitating role of macrophages, involving, for example, transformation or fusion hybridization with neoplastic cells. In this paradigm, tumor-secreted extracellular vesicles (EVs), such as exosomes, play a pivotal role in cell communications, delivering a plethora of biomolecules including proteins, lipids, and nucleic acids. For their natural role in shuttling molecules, EVs have been newly considered a part of the metastatic cascade. They have a prominent role in preparing the so-called “tumor niches” in target organs. However, recent evidence has pointed out an even more interesting role of tumor EVs, consisting in their ability to induce malignant transformation in resident mesenchymal stem cells. All in all, in this review, we discuss the multiple involvements of EVs in the metastatic cascade, and how we can exploit and manipulate EVs in order to reduce the metastatic spread of malignant tumors.

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N-cadherin in cancer dormancy

Cell death in therapy ◽

10.1515/cdth-2015-0002 ◽

2015 ◽

Vol 1 (1) ◽

Cited By ~ 2

Author(s):

Garima Sinha ◽

Pranela Rameshwar

Keyword(s):

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Signaling Cascades ◽

Intercellular Interaction ◽

Adhesion Protein ◽

Mesenchymal Transition ◽

Cycle Arrest ◽

Cancer Dormancy ◽

Rho Family

AbstractN-cadherin is an adhesion protein, which is important for intercellular interaction. It is involved in cell migration and motility during embryonic development, neuronal synapsis and cancer metastasis. There are several signaling cascades affected by N-cadherin including TGF-β, Rho family. N-cadherin is associated at the cytoplasmic domain with catenins (α, β, γ and p120) to facilitate metastasis. An increase in N-cadherin with down regulation of E-cadherin occurs during epithelial mesenchymal transition. Overexpression of N-cadherin is associated with cell cycle arrest, which correlates with a similar property of cancer stem cells (CSC). Connexin expression, which is important in CSC dormancy, is regulated by N-cadherin. This review discusses the potential of N-cadherin to be involved in maintaining CSCs, and to investigate pathways in N-cadherin expression. A better understanding of the role of N-Cadherin in CSC biology may identify new targets for the treatment of cancer.

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Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

Cancers ◽

10.3390/cancers13194985 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4985

Author(s):

Saima Usman ◽

Naushin H. Waseem ◽

Thuan Khanh Ngoc Nguyen ◽

Sahar Mohsin ◽

Ahmad Jamal ◽

...

Keyword(s):

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Cells ◽

Type I ◽

Mortality And Morbidity ◽

Mesenchymal Transition ◽

Type Iii ◽

Tumour Spread ◽

Molecular Events

Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis (type III). It is a multifaceted phenomenon governed by the activation of genes associated with cell migration, extracellular matrix degradation, DNA repair, and angiogenesis. The cancer cells employ EMT to acquire the ability to migrate, resist therapeutic agents and escape immunity. One of the key biomarkers of EMT is vimentin, a type III intermediate filament that is normally expressed in mesenchymal cells but is upregulated during cancer metastasis. This review highlights the pivotal role of vimentin in the key events during EMT and explains its role as a downstream as well as an upstream regulator in this highly complex process. This review also highlights the areas that require further research in exploring the role of vimentin in EMT. As a cytoskeletal protein, vimentin filaments support mechanical integrity of the migratory machinery, generation of directional force, focal adhesion modulation and extracellular attachment. As a viscoelastic scaffold, it gives stress-bearing ability and flexible support to the cell and its organelles. However, during EMT it modulates genes for EMT inducers such as Snail, Slug, Twist and ZEB1/2, as well as the key epigenetic factors. In addition, it suppresses cellular differentiation and upregulates their pluripotent potential by inducing genes associated with self-renewability, thus increasing the stemness of cancer stem cells, facilitating the tumour spread and making them more resistant to treatments. Several missense and frameshift mutations reported in vimentin in human cancers may also contribute towards the metastatic spread. Therefore, we propose that vimentin should be a therapeutic target using molecular technologies that will curb cancer growth and spread with reduced mortality and morbidity.

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SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.682773 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lei Lv ◽

Qiyi Yi ◽

Ying Yan ◽

Fengmei Chao ◽

Ming Li

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Migration And Invasion ◽

Akt Inhibitor ◽

Colon Adenoma ◽

Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

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Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0908133107 ◽

2010 ◽

Vol 107 (6) ◽

pp. 2485-2490 ◽

Cited By ~ 155

Author(s):

D. Xie ◽

C. Gore ◽

J. Liu ◽

R.-C. Pong ◽

R. Mason ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Prostate Cancer Metastasis

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The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition

Cells Tissues Organs ◽

10.1159/000512277 ◽

2020 ◽

pp. 1-23

Author(s):

Divya Adiga ◽

Raghu Radhakrishnan ◽

Sanjiban Chakrabarty ◽

Prashant Kumar ◽

Shama Prasada Kabekkodu

Keyword(s):

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Cancer Therapeutics ◽

Growth And Survival ◽

Mesenchymal Transition ◽

Microenvironmental Factors ◽

Favorable Clinical Outcome

Despite substantial advances in the field of cancer therapeutics, metastasis is a significant challenge for a favorable clinical outcome. Epithelial to mesenchymal transition (EMT) is a process of acquiring increased motility, invasiveness, and therapeutic resistance by cancer cells for their sustained growth and survival. A plethora of intrinsic mechanisms and extrinsic microenvironmental factors drive the process of cancer metastasis. Calcium (Ca2+) signaling plays a critical role in dictating the adaptive metastatic cell behavior comprising of cell migration, invasion, angiogenesis, and intravasation. By modulating EMT, Ca2+ signaling can regulate the complexity and dynamics of events leading to metastasis. This review summarizes the role of Ca2+ signal remodeling in the regulation of EMT and metastasis in cancer.

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