scholarly journals Plasmalemmal V-ATPase as a Potential Biomarker for Lactoferrin-Based Anticancer Therapy

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 119
Author(s):  
Cátia Santos-Pereira ◽  
Lígia R. Rodrigues ◽  
Manuela Côrte-Real
Keyword(s):  
Plasma Membrane ◽  
Cancer Cells ◽  
Proton Pump ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Future Research ◽  
Good Tolerability ◽  
Potential Biomarker ◽  
Health Promoting ◽  
Preclinical And Clinical Studies

Lactoferrin (Lf) is a milk-derived protein with well-recognized potential as a therapeutic agent against a wide variety of cancers. This natural protein exhibits health-promoting effects and has several interesting features, including its selectivity towards cancer cells, good tolerability in humans, worldwide availability, and holding a generally recognized as safe (GRAS) status. To prompt the rational clinical application of this promising anticancer compound, previous works aimed to unveil the molecular mechanisms underlying its selective anticancer activity, where plasmalemmal V-ATPase was identified as an Lf target in cancer cells. V-ATPase is a proton pump critical for cellular homeostasis that migrates to the plasma membrane of highly metastatic cancer cells contributing to the acidity of the tumor microenvironment. Cancer cells were found to be susceptible to Lf only when this proton pump is present at the plasma membrane. Plasmalemmal V-ATPase can thus be an excellent biomarker for driving treatment decisions and forecasting clinical outcomes of Lf-based anticancer strategies. Future research endeavors should thus seek to validate this biomarker by thorough preclinical and clinical studies, as well as to develop effective methods for its detection under clinical settings.

scholarly journals Regulation of ATP utilization during metastatic cell migration by collagen architecture

2018 ◽  
Vol 29 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Matthew R. Zanotelli ◽  
Zachary E. Goldblatt ◽  
Joseph P. Miller ◽  
Francois Bordeleau ◽  
Jiahe Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Three Dimensional ◽  
Migration And Invasion ◽  
Energy Regulation ◽  
Cancer Cell Migration ◽  
In Cells

Cell migration in a three-dimensional matrix requires that cells either remodel the surrounding matrix fibers and/or squeeze between the fibers to move. Matrix degradation, matrix remodeling, and changes in cell shape each require cells to expend energy. While significant research has been performed to understand the cellular and molecular mechanisms guiding metastatic migration, less is known about cellular energy regulation and utilization during three-dimensional cancer cell migration. Here we introduce the use of the genetically encoded fluorescent biomarkers, PercevalHR and pHRed, to quantitatively assess ATP, ADP, and pH levels in MDA-MB-231 metastatic cancer cells as a function of the local collagen microenvironment. We find that the use of the probe is an effective tool for exploring the thermodynamics of cancer cell migration and invasion. Specifically, we find that the ATP:ADP ratio increases in cells in denser matrices, where migration is impaired, and it decreases in cells in aligned collagen matrices, where migration is facilitated. When migration is pharmacologically inhibited, the ATP:ADP ratio decreases. Together, our data indicate that matrix architecture alters cellular energetics and that intracellular ATP:ADP ratio is related to the ability of cancer cells to effectively migrate.

scholarly journals The role of redox system in metastasis formation

Angiogenesis ◽  
2021 ◽  
Author(s):  
Chiara Cencioni ◽  
Valentina Comunanza ◽  
Emanuele Middonti ◽  
Edoardo Vallariello ◽  
Federico Bussolino
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Special Focus ◽  
Oxygen Species ◽  
Metastasis Formation ◽  
Radical Oxygen Species ◽  
Cancer Disease ◽  
Metastatic Cancer Cells

AbstractThe metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites.

scholarly journals Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling

2006 ◽  
Vol 394 (3) ◽  
pp. 647-656 ◽  
Author(s):  
Kengo Kato ◽  
Kiyoto Shiga ◽  
Kazunori Yamaguchi ◽  
Keiko Hata ◽  
Toshimitsu Kobayashi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Plasma Membrane ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Human Colon ◽  
Human Colon Cancer ◽  
Laminin 5 ◽  
Colon Cancers ◽  
Integrin Β4

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin β4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin β4) antibody, suggesting that association of NEU3 with integrin β4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin β1 and ILK (integrin-linked kinase) was also observed on laminins. GM3 depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin – NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.

scholarly journals Vimentin on the move: new developments in cell migration

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1796 ◽  
Author(s):  
Rachel A. Battaglia ◽  
Samed Delic ◽  
Harald Herrmann ◽  
Natasha T. Snider
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cell Biology ◽  
Wound Repair ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Building Blocks ◽  
Mesenchymal Transition ◽  
New Findings

The vimentin gene (VIM) encodes one of the 71 human intermediate filament (IF) proteins, which are the building blocks of highly ordered, dynamic, and cell type-specific fiber networks. Vimentin is a multi-functional 466 amino acid protein with a high degree of evolutionary conservation among vertebrates. Vim−/− mice, though viable, exhibit systemic defects related to development and wound repair, which may have implications for understanding human disease pathogenesis. Vimentin IFs are required for the plasticity of mesenchymal cells under normal physiological conditions and for the migration of cancer cells that have undergone epithelial–mesenchymal transition. Although it was observed years ago that vimentin promotes cell migration, the molecular mechanisms were not completely understood. Recent advances in microscopic techniques, combined with computational image analysis, have helped illuminate vimentin dynamics and function in migrating cells on a precise scale. This review includes a brief historical account of early studies that unveiled vimentin as a unique component of the cell cytoskeleton followed by an overview of the physiological vimentin functions documented in studies on Vim−/− mice. The primary focus of the discussion is on novel mechanisms related to how vimentin coordinates cell migration. The current hypothesis is that vimentin promotes cell migration by integrating mechanical input from the environment and modulating the dynamics of microtubules and the actomyosin network. These new findings undoubtedly will open up multiple avenues to study the broader function of vimentin and other IF proteins in cell biology and will lead to critical insights into the relevance of different vimentin levels for the invasive behaviors of metastatic cancer cells.

scholarly journals Quantitative Proteomics Reveals Regulation of Karyopherin Subunit Alpha-2 (KPNA2) and Its Potential Novel Cargo Proteins in Nonsmall Cell Lung Cancer

2012 ◽  
Vol 11 (11) ◽  
pp. 1105-1122 ◽  
Author(s):  
Chun-I Wang ◽  
Kun-Yi Chien ◽  
Chih-Liang Wang ◽  
Hao-Ping Liu ◽  
Chia-Chen Cheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Isotope Labeling ◽  
Nonsmall Cell Lung Cancer ◽  
Lung Cancer Cells ◽  
Mrna Levels ◽  
Potential Biomarker ◽  
Cargo Proteins

The process of nucleocytoplasmic shuttling is mediated by karyopherins. Dysregulated expression of karyopherins may trigger oncogenesis through aberrant distribution of cargo proteins. Karyopherin subunit alpha-2 (KPNA2) was previously identified as a potential biomarker for nonsmall cell lung cancer by integration of the cancer cell secretome and tissue transcriptome data sets. Knockdown of KPNA2 suppressed the proliferation and migration abilities of lung cancer cells. However, the precise molecular mechanisms underlying KPNA2 activity in cancer remain to be established. In the current study, we applied gene knockdown, subcellular fractionation, and stable isotope labeling by amino acids in cell culture-based quantitative proteomic strategies to systematically analyze the KPNA2-regulating protein profiles in an adenocarcinoma cell line. Interaction network analysis revealed that several KPNA2-regulating proteins are involved in the cell cycle, DNA metabolic process, cellular component movements and cell migration. Importantly, E2F1 was identified as a potential novel cargo of KPNA2 in the nuclear proteome. The mRNA levels of potential effectors of E2F1 measured using quantitative PCR indicated that E2F1 is one of the “master molecule” responses to KPNA2 knockdown. Immunofluorescence staining and immunoprecipitation assays disclosed co-localization and association between E2F1 and KPNA2. An in vitro protein binding assay further demonstrated that E2F1 interacts directly with KPNA2. Moreover, knockdown of KPNA2 led to subcellular redistribution of E2F1 in lung cancer cells. Our results collectively demonstrate the utility of quantitative proteomic approaches and provide a fundamental platform to further explore the biological roles of KPNA2 in nonsmall cell lung cancer.

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