scholarly journals Identification of potential inhibitory analogs of metastasis tumor antigens (MTAs) using bioactive compounds: revealing therapeutic option to prevent malignancy

2020 ◽  
Author(s):  
Anik Banik ◽  
Sheikh Rashel Ahmed ◽  
Emran Hossain Sajib ◽  
Anamika Deb ◽  
Shiuly Sinha ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Tumor Antigens ◽  
Early Stage ◽  
Therapeutic Option ◽  
Asiatic Acid ◽  
Plant Metabolites

AbstractThe deeper understanding of metastasis phenomenon and detection of drug targets could be a potential approach to minimize cancer mortality. In this study, attempts were taken to unmask novel therapeutics to prevent metastasis and cancer progression. Initially, we explored the physiochemical, structural and functional insights of three metastasis tumor antigens (MTAs) and evaluated some plant based bioactive compounds as potent MTA inhibitors. From 50 plant metabolites screened, isoflavone, gingerol, citronellal and asiatic acid showed maximum binding affinity with all three MTA proteins. The ADME analysis detected no undesirable toxicity that could reduce the drug likeness properties of top plant metabolites. Moreover, molecular dynamics studies revealed that the complexes were stable and showed minimum fluctuation at molecular level. We further performed ligand based virtual screening to identify similar drug molecules using a large collection of 3,76,342 compounds from DrugBank. The results suggested that several structural analogs (e.g. Tramadol, Nabumetone, DGLA, Hydrocortisone) may act as agonist to block the MTA proteins and inhibit cancer progression at early stage. The study could be useful to develop effective medications against cancer metastasis in future. Due to encouraging results, we highly recommend further in vitro and in vivo trials for the experimental validation of the findings.

scholarly journals lncRNA NORAD Contributes to Colorectal Cancer Progression by Inhibition of miR-202-5p

2018 ◽  
Vol 26 (9) ◽  
pp. 1411-1418 ◽  
Author(s):  
Jie Zhang ◽  
Xiao-Yan Li ◽  
Ping Hu ◽  
Yuan-Sheng Ding
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Competing Endogenous Rna

Previous study indicates that long noncoding RNA NORAD could serve as a competing endogenous RNA to pancreatic cancer metastasis. However, its role in colorectal cancer (CRC) needs to be investigated. In the present study, we found that the expression of NORAD was significantly upregulated in CRC tissues. Furthermore, the expression of NORAD was positively related with CRC metastasis and patients’ poor prognosis. Knockdown of NORAD markedly inhibited CRC cell proliferation, migration, and invasion but induced cell apoptosis in vitro. In vivo experiments also indicated an inhibitory effect of NORAD on tumor growth. Mechanistically, we found that NORAD served as a competing endogenous RNA for miR-202-5p. We found that there was an inverse relationship between the expression of NORAD and miR-202-5p in CRC tissues. Moreover, overexpression of miR-202-5p in SW480 and HCT116 cells significantly inhibited cellular proliferation, migration, and invasion. Taken together, our study demonstrated that the NORAD/miR-202-5p axis plays a pivotal function on CRC progression.

scholarly journals Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

2021 ◽  
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Pancreatic Cancer ◽  
Survival Time ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

scholarly journals RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

2020 ◽  
Author(s):  
Yiwu Yan ◽  
Bo Zhou ◽  
Chen Qian ◽  
Alex Vasquez ◽  
Avradip Chatterjee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Drug Targets ◽  
Cancer Metastasis ◽  
Therapeutic Interventions ◽  
Interacting Protein ◽  
Prostate Cancer Metastasis ◽  
Prostate Cancers

AbstractDespite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

scholarly journals Human Polyomaviruses: The Battle of Large and Small Tumor Antigens

2017 ◽  
Vol 8 ◽  
pp. 1178122X1774478 ◽  
Author(s):  
Camila Freze Baez ◽  
Rafael Brandão Varella ◽  
Sonia Villani ◽  
Serena Delbue
Keyword(s):  
Tumor Antigens ◽  
Early Stage ◽  
Short Review ◽  
Viral Dna Replication ◽  
Virion Assembly ◽  
Small Tumor ◽  
Functional Features ◽  
Human Polyomaviruses

About 40 years ago, the large and small tumor antigens (LT-Ag and sT-Ag) of the polyomavirus (PyVs) simian vacuolating virus 40 have been identified and characterized. To date, it is well known that all the discovered human PyVs (HPyVs) encode these 2 multifunctional and tumorigenic proteins, expressed at viral replication early stage. The 2 T-Ags are able to transform cells both in vitro and in vivo and seem to play a distinct role in the pathogenesis of some tumors in humans. In addition, they are involved in viral DNA replication, transcription, and virion assembly. This short review focuses on the structural and functional features of the HPyVs’ LT-Ag and sT-Ag, with special attention to their transforming properties.

scholarly journals Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis

2018 ◽  
Author(s):  
Minoru Inoue ◽  
Masahiro Enomoto ◽  
Yuhki Koike ◽  
Marco A. Di Grappa ◽  
Xiao Zhao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cancer Metastasis ◽  
Redox Balance ◽  
Redox Imbalance ◽  
Free Thiol ◽  
Pulmonary Cancer ◽  
Inflammatory Stimuli ◽  
Pharmacologic Inhibition

AbstractNeutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.

scholarly journals Upregulation of LGALS1 is associated with oral cancer metastasis

2018 ◽  
Vol 10 ◽  
pp. 175883591879462 ◽  
Author(s):  
Ji-Min Li ◽  
Chien-Wei Tseng ◽  
Chi-Chen Lin ◽  
Ching-Hsuan Law ◽  
Yu-An Chien ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Mapk Pathway ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Oral Cancer Cells

Background: Oral cancer metastasis is a devastating process that contributes to poor prognosis and high mortality, yet its detailed underlying mechanisms remain unclear. Here, we aimed to evaluate metastasis-specific markers in oral cancer and to provide comprehensive recognition concerning functional roles of the specific target in oral cancer metastasis. Methods: Lectin, galactoside-binding, soluble, 1 (LGALS1) was identified by secretomic analysis. LGALS1 expression of patient samples with oral cancer on the tissue microarray were examined by immunochemical (IHC) staining. Small interfering RNA (siRNA)-mediated knockdown of LGALS1 revealed the role of LGALS1 in oral cancer metastasis in vitro and in vivo. Results: LGALS1 was observed to be upregulated in highly invasive oral cancer cells, and elevated LGALS1 expression was correlated with cancer progression and lymph node metastasis in oral cancer tissue specimens. Functionally, silencing LGALS1 resulted in suppressed cell growth, wound healing, cell migration, and cell invasion in oral cancer cells in vitro. Knockdown of LGALS1 in highly invasive oral cancer cells dramatically inhibited lung metastasis in an in vivo mouse model. Mechanistic studies suggested p38 mitogen-activated protein kinase (MAPK) phosphorylation, upregulated MMP-9, and mesenchymal phenotypes of epithelial-mesenchymal transition (EMT) in highly invasive oral cancer cells, whereas siRNA against LGALS1 resulted in the inactivation of p38 MAPK pathway, downregulated MMP-9, and EMT inhibition. Conclusions: These findings demonstrate that elevated LGALS1 is strongly correlated with oral cancer progression and metastasis, and that it could potentially serve as a prognostic biomarker and an innovative target for oral cancer therapy.

scholarly journals Effect of Zinc Supplementation on the Serum Metabolites Profile at the Early Stage of Breast Cancer in Rats

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3457
Author(s):  
Barbara Bobrowska-Korczak ◽  
Paulina Gątarek ◽  
Dorota Skrajnowska ◽  
Wojciech Bielecki ◽  
Rafal Wyrebiak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Dietary Intervention ◽  
Early Stage ◽  
Chemical Induction ◽  
Zinc Nanoparticles ◽  
Potential Therapeutic Application

The cytotoxic properties of zinc nanoparticles have been evaluated in vitro against several types of cancer. However, there is a lack of significant evidence of their activity in vivo, and a potential therapeutic application remains limited. Herein we report the effective inhibition of tumor growth by zinc nanoparticles in vivo, as the effect of the dietary intervention, after the chemical induction in a rodent model of breast cancer. Biopsy images indicated grade 1 tumors with multiple inflammatory infiltrates in the group treated with zinc nanoparticles, whereas, in the other groups, a moderately differentiated grade 2 adenocarcinoma was identified. Moreover, after the supplementation with zinc nanoparticles, the levels of several metabolites associated with cancer metabolism, important to its survival, were found to have been altered. We also revealed that the biological activity of zinc in vivo depends on the size of applied particles, as the treatment with zinc microparticles has not had much effect on cancer progression.

scholarly journals ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis

2018 ◽  
Vol 115 (41) ◽  
pp. E9580-E9589 ◽  
Author(s):  
Jordan M. Reese ◽  
Elizabeth S. Bruinsma ◽  
Adam W. Nelson ◽  
Igor Chernukhin ◽  
Jason S. Carroll ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Tgfβ Signaling

Triple-negative breast cancer (TNBC) accounts for a disproportionately high number of deaths due to a lack of targeted therapies and an increased likelihood of distant recurrence. Estrogen receptor beta (ERβ), a well-characterized tumor suppressor, is expressed in 30% of TNBCs, and its expression is associated with improved patient outcomes. We demonstrate that therapeutic activation of ERβ elicits potent anticancer effects in TNBC through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFβ signaling and suppress metastatic phenotypes both in vitro and in vivo. These data reveal the involvement of cystatins in suppressing breast cancer progression and highlight the value of ERβ-targeted therapies for the treatment of TNBC patients.

scholarly journals TFEB Promotes Prostate Cancer Progression via Regulating ABCA2-Dependent Lysosomal Biogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xuejin Zhu ◽  
Yangjia Zhuo ◽  
Shulin Wu ◽  
Yanfei Chen ◽  
Jianheng Ye ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Macrophage Polarization ◽  
Clinical Value ◽  
Tissue Samples ◽  
Invasion And Migration

Transcription factor EB (TFEB), a member of the MiT family, is dysregulated in different cancers and exerts specific biological functions within the tumor microenvironment. Downregulation of TFEB induces macrophage polarization in the TME and promotes tumor progression. However, the biological role and clinical significance of TFEB in prostate cancer (PCa) remain unknown. This study aimed to identify the role of TFEB in PCa and its potential clinical value. We explored TFEB expression in PCa using public databases and verified its prognostic value using immunohistochemistry in PCa tissue samples. The results revealed that TFEB expression was up-regulated in PCa tissues and was associated with cancer metastasis. Next, overexpression of TFEB promoted PCa cell malignant behavior in in vivo and in vitro experiments. RNA-sequencing and bioinformatics analysis showed high expression of TFEB promoted lysosomal biogenesis and knockdown of TFEB expression decreased the number of lysosomes. Furthermore, the ATP-binding cassette transporter A2 (ABCA2) was identified as a target gene of TFEB, which was verified using the cleavage under targets and release using nuclease (CUT&RUN) assay and qRT-PCR. Silencing of ABCA2 reduced lysosomal biogenesis and decreased matrix metalloproteinases expression, which reduced PCa cell invasion and migration in the tumor microenvironment. Our study suggests that TFEB promotes PCa progression by regulating ABCA2 through lysosomal biogenesis and may serve as a prognostic factor or as a potential therapeutic target of PCa.

scholarly journals The Impact of Coffee and Its Selected Bioactive Compounds on the Development and Progression of Colorectal Cancer In Vivo and In Vitro

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3309 ◽  
Author(s):  
Rafał J. Bułdak ◽  
Tomasz Hejmo ◽  
Marcin Osowski ◽  
Łukasz Bułdak ◽  
Michał Kukla ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Caffeic Acid ◽  
Bioactive Compounds ◽  
Cancer Progression ◽  
Coffee Consumption ◽  
Biologically Active ◽  
Chlorogenic Acids ◽  
The Impact

Coffee is one of the most popular beverages worldwide. Coffee contains bioactive compounds that affect the human body such as caffeine, caffeic acid, chlorogenic acids, trigonelline, diterpenes, and melanoidins. Some of them have demonstrated potential anticarcinogenic effects in animal models and in human cell cultures, and may play a protective role against colorectal cancer. Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the USA and other countries. Dietary patterns, as well as the consumption of beverages, may reduce the risk of CRC incidence. In this review, we focus on published epidemiological studies concerning the association of coffee consumption and the risk of development of colorectal cancer, and provide a description of selected biologically active compounds in coffee that have been investigated as potential cancer-combating compounds: Caffeine, caffeic acid (CA), chlorogenic acids (CGAs), and kahweol in relation to colorectal cancer progression in in vitro settings. We review the impact of these substances on proliferation, viability, invasiveness, and metastasis, as well as on susceptibility to chemo- and radiotherapy of colorectal cancer cell lines cultured in vitro.

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