scholarly journals The Role of Rho GTPases in VEGF Signaling in Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Nada El Baba ◽  
Mohammad Farran ◽  
Elie Abi Khalil ◽  
Leila Jaafar ◽  
Isabelle Fakhoury ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Transmembrane Receptors ◽  
Vegf Signaling ◽  
Endothelial Growth Factors

Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules’ binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.

Oncometabolite succinate to promote angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23000-e23000
Author(s):  
Xianmin Mu ◽  
Ting Zhao ◽  
Che Xu ◽  
Wei Shi ◽  
Biao Geng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Structure Formation ◽  
Tumor Angiogenesis ◽  
Cancer Metabolism ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Vessel Formation

e23000 Background: Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers has been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Methods: Succinate levels were measured in gastric cancer and paracancerous tissues as well as cell culture supernatants from normal cells and gastric cancer cells. Chemotactic motility, capillary structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) were determined in the presence of succinate in vitro. Moreover, the vessel formation in zebrafish embryo was also used to examine the effect of succinate on angiogenesis. The activation of STAT3 and ERK signaling by succinate was checked by Western Blot. Results: Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of pHUVECs in vitro, as well as promote the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Conclusions: These data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.

scholarly journals The role of vascular endothelial growth factor in the regulation of development and functioning of the brain: new target molecules for pharmacotherapy

2016 ◽  
Vol 62 (2) ◽  
pp. 124-133 ◽  
Author(s):  
V.V. Roslavtceva ◽  
A.B. Salmina ◽  
S.V. Prokopenko ◽  
E.A. Pozhilenkova ◽  
I.V. Kobanenko ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Neurological Diseases ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Target Molecules ◽  
Endothelial Growth Factor ◽  
Endothelial Growth Factors ◽  
The Brain

Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair. Most of these actions involve VEGF-A and the VEGFR-2 receptor. VEGF signaling pathways represent an important potential for treatment of neurological diseases affecting the brain

scholarly journals An Inside View: VEGF Receptor Trafficking and Signaling

Physiology ◽  
2012 ◽  
Vol 27 (4) ◽  
pp. 213-222 ◽  
Author(s):  
Michael Simons
Keyword(s):  
Control Systems ◽  
Biological Function ◽  
Critical Role ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Receptor Endocytosis ◽  
Vegf Signaling ◽  
Adult Organism ◽  
Endothelial Growth Factors

Vascular endothelial growth factors (VEGF) and their receptors play a central role in the development of cardiovascular system and in vasculature-related processes in the adult organism. Given the critical role of this signaling cascade, intricate control systems have evolved to regulate its function. A new layer of added complexity has been the demonstration of the importance of endocytosis and intracellular trafficking of VEGF receptors in the regulation of VEGF signaling. In this review, we consider an evolving link between VEGF receptor endocytosis, trafficking, and signaling and their biological function.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 89
Author(s):  
Ha Thi Thu Do ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

scholarly journals Hypermethylated miR-424 in Colorectal Cancer Subsequently Upregulates VEGF

2021 ◽  
Author(s):  
Zahra Nouri Ghonbalani ◽  
Shiva Shahmohamadnejad ◽  
Parvin Pasalar ◽  
Ehsan Khalili
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Promoter Region ◽  
Hct116 Cell ◽  
Methylation Status ◽  
Expression Level ◽  
Cancer Tissue ◽  
Vegf Expression ◽  
Cancer Tissues

Abstract PurposeColorectal cancer (CRC) is the second leading cause of death from cancer in adults. Recent advances have shown that cancer cells can have some epigenetic changes involved in all stages of cancer. It has also been shown that miR-424 acts as gene expression regulators in many biological processes, including angiogenesis with mediators such as VEGF. In the current study, to identify the potential role of miR-424 in colorectal cancer progression, methylation status of miR-424 promoter region and its expression level have been evaluated. Besides, the correlation between VEGF level and miR-424 expression level has been assessed.MethodsMethylation status miR-424 promoter was assessed using methylation-specific polymerase chain reaction (MSP). The expression level of miR-424 in human colorectal cancer tissue was analyzed by quantitative PCR. HCT116 cell line was selected to evaluate the correlation between the miR-424 expression level and the promoter's methylation status. VEGF expression, one out of mir-424 targets involved in angiogenesis and cancer progression, was measured by western blot analysis in the pairs of cancer tissues and their adjacent tissues.ResultsOur results have revealed that the promoter region of miR-424 is methylated in cancer cells compared to normal cells, leading to down-regulation of miR-424 in the colorectal cancer tissues compared to the normal tissues. Also, we found that the expression protein's level of VEGF in the tumor cells increased compared with normal tissues.ConclusionThe present study suggests that hypermethylation downregulates miR-424. VEGF expression is upregulated with decreased miR-424 in colorectal cancer, which results in cancer progression.

scholarly journals The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer

2014 ◽  
Vol 60 (3) ◽  
pp. 322-331 ◽  
Author(s):  
E.A. Avilova ◽  
O.E. Andreeva ◽  
V.A. Shatskaya ◽  
M.A. Krasilnikov
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Cell Lines ◽  
Hormone Resistance ◽  
Mesenchymal Transition

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: a Perspective on the Role of PPT1 Enzyme

2021 ◽  
Vol 22 ◽  
Author(s):  
Diana Duarte ◽  
Nuno Vale
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Antineoplastic Agents ◽  
Antimalarial Drugs ◽  
Antineoplastic Drugs ◽  
Anticancer Effects ◽  
Different Types ◽  
Important Pathway ◽  
Palmitoyl Protein Thioesterase

: Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon, etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here, we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of antimalarial and antineoplastic agents in cancer cells.

scholarly journals Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 692 ◽  
Author(s):  
Elisabete Cruz da Silva ◽  
Monique Dontenwill ◽  
Laurence Choulier ◽  
Maxime Lehmann
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Cancer Cell Proliferation ◽  
Remarkable Feature ◽  
Rtk Signaling ◽  
Intracellular Signal ◽  
New Treatment

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.

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