scholarly journals RAC1 Takes the Lead in Solid Tumors

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 382 ◽  
Author(s):  
Pradip De ◽  
Jennifer Carlson Aske ◽  
Nandini Dey
Keyword(s):  
Drug Resistance ◽  
Embryonic Development ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Cellular Localization ◽  
Regulatory Mechanisms ◽  
Cellular Functions ◽  
Patterns Of Distribution ◽  
Background Data

Three GTPases, RAC, RHO, and Cdc42, play essential roles in coordinating many cellular functions during embryonic development, both in healthy cells and in disease conditions like cancers. We have presented patterns of distribution of the frequency of RAC1-alteration(s) in cancers as obtained from cBioPortal. With this background data, we have interrogated the various functions of RAC1 in tumors, including proliferation, metastasis-associated phenotypes, and drug-resistance with a special emphasis on solid tumors in adults. We have reviewed the activation and regulation of RAC1 functions on the basis of its sub-cellular localization in tumor cells. Our review focuses on the role of RAC1 in cancers and summarizes the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of RAC1-PAK targeting agents.

TRiC-P5, a novel TCP1-related protein, is localized in the cytoplasm and in the nuclear matrix

1994 ◽  
Vol 107 (10) ◽  
pp. 2851-2859
Author(s):  
E.C. Joly ◽  
E. Tremblay ◽  
R.M. Tanguay ◽  
Y. Wu ◽  
V. Bibor-Hardy
Keyword(s):  
Nuclear Matrix ◽  
Cellular Localization ◽  
Cell Fractionation ◽  
Cellular Functions ◽  
Raji Cells ◽  
T Complex ◽  
Ring Complex ◽  
Filament Network ◽  
Novel Protein

We have recently reported the cloning of a novel protein, TRiC-P5, with significant homology with protein 1 of the t-complex (TCP1). In the present study, the cellular localization of TRiC-P5 in Raji cells has been determined using an antiserum raised against a 18.5 kDa fusion protein. Results from cell fractionation and immunoblot studies indicate that TRiC-P5 is mainly localized in the cytoplasm. In addition, a significant part of TRiC-P5 is also found in the nucleus where it is attached to the nuclear matrix, a complex filament network involved in essential cellular functions such as DNA replication, and RNA transcription and maturation. Immunofluorescence experiments using the anti-TRiC-P5 antibodies confirm these results. We also provide evidence that, in the cytoplasm, TRiC-P5 is part of a large protein complex, most probably the TCP1-ring complex (TRiC), a hetero-oligomeric ring complex that plays a role of molecular chaperone in the folding of actin and tubulin.

scholarly journals CD133 in Breast Cancer Cells: More than a Stem Cell Marker

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Federica Brugnoli ◽  
Silvia Grassilli ◽  
Yasamin Al-Qassab ◽  
Silvano Capitani ◽  
Valeria Bertagnolo
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Breast Tumors ◽  
Surface Expression ◽  
Stem Cell Marker ◽  
Industrialized Countries ◽  
Triple Negative Phenotype

Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in industrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. The molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors.

Phosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences

2017 ◽  
Vol 474 (17) ◽  
pp. 2903-2924 ◽  
Author(s):  
Matthias Dedobbeleer ◽  
Estelle Willems ◽  
Stephen Freeman ◽  
Arnaud Lombard ◽  
Nicolas Goffart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Solid Tumors ◽  
Primary Cancer ◽  
Key Factors ◽  
Cellular Functions ◽  
The Central Nervous System ◽  
Differentiation And Proliferation ◽  
Shed Light

Phosphatases and cancer have been related for many years now, as these enzymes regulate key cellular functions, including cell survival, migration, differentiation and proliferation. Dysfunctions or mutations affecting these enzymes have been demonstrated to be key factors for oncogenesis. The aim of this review is to shed light on the role of four different phosphatases (PTEN, PP2A, CDC25 and DUSP1) in five different solid tumors (breast cancer, lung cancer, pancreatic cancer, prostate cancer and ovarian cancer), in order to better understand the most frequent and aggressive primary cancer of the central nervous system, glioblastoma.

Potential Role of Dual NF-κB and Oxidative Stress Pathway Inhibitor, OT-304 as a Novel Drug Resistance-Reversing Agent.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4211-4211
Author(s):  
Shaker A. Mousa ◽  
Ghanshyam Patil ◽  
Abdelhadi Rebbaa
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Genetic Alterations ◽  
Potential Candidate ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
And Oxidative Stress

Abstract The development of resistance to chemotherapy represents an adaptive biological response by tumor cells that leads to treatment failure and patient relapse. During the course of their evolution (intrinsic resistance) or in response to chemotherapy (acquired resistance), tumor cells may undergo genetic alterations to possess a drug resistant phenotype. Dysregulation of membrane transport proteins and cellular enzymes, as well as altered susceptibility to commit to apoptosis are among the mechanisms that contribute to the genesis of acquired drug resistance. Recently, the development of approaches to prevent and/or to reverse this phenomenon has attracted special interest and a number of drug candidates have been identified. Despite strong effects observed for these candidates in vitro, however, most of them fail in vivo. In the present study, we have identified a novel small molecule inhibitor of dual NF-κB and oxidative stress pathways, OT-304, as a potential candidate to reverse drug resistance. Initial investigations indicate that this compound effectively inhibits proliferation of doxorubicin-sensitive and doxorubicin-resistant cells to the same extent, suggesting that it is capable of bypassing the development of drug resistance. Additional experiments reveal that OT-304 enhances cancer cell sensitivity to doxorubicin and to etoposide, particularly in cells characterized by the over-expression of the drug transporter P-glycoprotein. These findings suggest that either the expression/and or the function of P-glycoprotein could be affected by OT-304. In vivo studies using tumor xenografts in nude mice showed that OT-304 is also capable of preventing the growth of drug resistant cancer cells. This later finding further confirms the role of OT-304 as a drug resistance-reversing agent and warrants further pre-clinical and clinical investigation to determine its efficacy in treating aggressive tumors.

scholarly journals Regulation of GSTu1-mediated insecticide resistance in Plutella xylostella by miRNA and lncRNA

PLoS Genetics ◽  
2021 ◽  
Vol 17 (10) ◽  
pp. e1009888
Author(s):  
Bin Zhu ◽  
Linhong Li ◽  
Rui Wei ◽  
Pei Liang ◽  
Xiwu Gao
Keyword(s):  
Drug Resistance ◽  
Insecticide Resistance ◽  
Plutella Xylostella ◽  
Mrna Stability ◽  
Noncoding Rna ◽  
Antisense Transcript ◽  
Regulatory Mechanisms ◽  
Detoxifying Enzymes ◽  
Evolution Of Resistance

The evolution of resistance to insecticides is well known to be closely associated with the overexpression of detoxifying enzymes. Although the role of glutathione S-transferase (GST) genes in insecticide resistance has been widely reported, the underlying regulatory mechanisms are poorly understood. Here, one GST gene (GSTu1) and its antisense transcript (lnc-GSTu1-AS) were identified and cloned, and both of them were upregulated in several chlorantraniliprole-resistant Plutella xylostella populations. GSTu1 was confirmed to be involved in chlorantraniliprole resistance by direct degradation of this insecticide. Furthermore, we demonstrated that lnc-GSTu1-AS interacted with GSTu1 by forming an RNA duplex, which masked the binding site of miR-8525-5p at the GSTu1-3′UTR. In summary, we revealed that lnc-GSTu1-AS maintained the mRNA stability of GSTu1 by preventing its degradation that could have been induced by miR-8525-5p and thus increased the resistance of P. xylostella to chlorantraniliprole. Our findings reveal a new noncoding RNA-mediated pathway that regulates the expression of detoxifying enzymes in insecticide-resistant insects and offer opportunities for the further understanding of the mechanisms of insecticide and drug resistance.

scholarly journals Rho–ROCK signaling regulates tumor-microenvironment interactions

2018 ◽  
Vol 47 (1) ◽  
pp. 101-108 ◽  
Author(s):  
Mohammad Zahied Johan ◽  
Michael S. Samuel
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Migration And Invasion ◽  
Cellular Functions ◽  
Cancer Cell Growth ◽  
Current State ◽  
Clinical Models ◽  
Endothelial Migration ◽  
Biophysical Interactions

Abstract Reciprocal biochemical and biophysical interactions between tumor cells, stromal cells and the extracellular matrix (ECM) result in a unique tumor microenvironment that determines disease outcome. The cellular component of the tumor microenvironment contributes to tumor growth by providing nutrients, assisting in the infiltration of immune cells and regulating the production and remodeling of the ECM. The ECM is a noncellular component of the tumor microenvironment and provides both physical and biochemical support to the tumor cells. Rho–ROCK signaling is a key regulator of actomyosin contractility and regulates cell shape, cytoskeletal arrangement and thereby cellular functions such as cell proliferation, differentiation, motility and adhesion. Rho–ROCK signaling has been shown to promote cancer cell growth, migration and invasion. However, it is becoming clear that this pathway also regulates key tumor-promoting properties of the cellular and noncellular components of the tumor microenvironment. There is accumulating evidence that Rho–ROCK signaling enhances ECM stiffness, modifies ECM composition, increases the motility of tumor-associated fibroblasts and lymphocytes and promotes trans-endothelial migration of tumor-associated lymphocytes. In this review, we briefly discuss the current state of knowledge on the role of Rho–ROCK signaling in regulating the tumor microenvironment and the implications of this knowledge for therapy, potentially via the development of selective inhibitors of the components of this pathway to permit the tuning of signaling flux, including one example with demonstrated utility in pre-clinical models.

scholarly journals Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yanjie Guan ◽  
Yifei Wang ◽  
Bo Li ◽  
Kai Shen ◽  
Quanfu Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Energy Production ◽  
Cellular Differentiation ◽  
Vital Role ◽  
Regulatory Mechanisms ◽  
Physiological Processes ◽  
Promising Strategy ◽  
New Frontier ◽  
Anticancer Therapeutics

AbstractThe mitochondrion is an organelle that plays a vital role in energy production, cytoplasmic protein degradation and cell death. Mitophagy is an autophagic procedure that specifically clears damaged mitochondria and maintains its homeostasis. Emerging evidence indicates that mitophagy is involved in many physiological processes, including cellular homeostasis, cellular differentiation and nerve protection. In this review, we describe the regulatory mechanisms of mitophagy in mammals and yeasts and highlight the recent advances relevant to its function in carcinogenesis and drug resistance. Finally, a section has been dedicated to describing the role of mitophagy in anticancer therapeutics, which is a new frontier that offers a precise and promising strategy.

Gene expression and cellular localization of ROMKs in the gills and kidney of Mozambique tilapia acclimated to fresh water with high potassium concentration

2014 ◽  
Vol 307 (11) ◽  
pp. R1303-R1312 ◽  
Author(s):  
Fumiya Furukawa ◽  
Soichi Watanabe ◽  
Keigo Kakumura ◽  
Junya Hiroi ◽  
Toyoji Kaneko
Keyword(s):  
Cellular Localization ◽  
Apical Membrane ◽  
Regulatory Mechanisms ◽  
Control Fish ◽  
Type I ◽  
High Potassium ◽  
Mozambique Tilapia ◽  
High K ◽  
High Potassium Concentration

Regulation of plasma K+ levels in narrow ranges is vital to vertebrate animals. Since seawater (SW) teleosts are loaded with excess K+, they constantly excrete K+ from the gills. However, the K+ regulatory mechanisms in freshwater (FW)-acclimated teleosts are still unclear. We aimed to identify the possible K+ regulatory mechanisms in the gills and kidney, the two major osmoregulatory organs, of FW-acclimated Mozambique tilapia ( Oreochromis mossambicus). As a potential molecular candidate for renal K+ handling, a putative renal outer medullary K+ channel (ROMK) was cloned from the tilapia kidney and tentatively named “ROMKb”; another ROMK previously cloned from the tilapia gills was thus renamed “ROMKa”. The fish were acclimated to control FW or to high-K+ (H-K) FW for 1 wk, and we assessed physiological responses of tilapia to H-K treatment. As a result, urinary K+ levels were slightly higher in H-K fish, implying a role of the kidney in K+ excretion. However, the mRNA expression levels of both ROMKa and ROMKb were very low in the kidney, while that of K+/Cl− cotransporter 1 (KCC1) was robust. In the gills, ROMKa mRNA was markedly upregulated in H-K fish. Immunofluorescence staining showed that branchial ROMKa was expressed at the apical membrane of type I and type III ionocytes, and the ROMKa immunosignals were more intense in H-K fish than in control fish. The present study suggests that branchial ROMKa takes a central role for K+ regulation in FW conditions and that K+ excretion via the gills is activated irrespective of environmental salinity.

scholarly journals Translocation of intracellular CD24 constitutes a triggering event for drug resistance in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hugo Werner Huth ◽  
Thiago Castro-Gomes ◽  
Alfredo Miranda de Goes ◽  
Catherine Ropert
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Membrane ◽  
Tumor Cells ◽  
P38 Mapk ◽  
Cellular Localization ◽  
Stem Cell Marker ◽  
Breast Cancer Cell Lines ◽  
Phenotype Switching

AbstractThe capacity of tumor cells to shift dynamically between different states could be responsible for chemoresistance and has been commonly linked to the acquisition of stem cell properties. Here, we have evaluated the phenotype switching associated with drug resistance in breast cancer cell lines and cell lineage obtained from Brazilian patients. We have highlighted the role of the cancer stem cell marker CD24 in the dynamics of cell plasticity and the acquirement of drug resistance. We showed that the translocation of CD24 from cytosol to cell membrane is a triggering event for the phenotype change of breast tumor cells exposed to drug stress. Here, we provide evidence that the phenotype switching is due to the presence of a cytosolic pool of CD24. Importantly, the cellular localization of CD24 was correlated with the changes in the dynamics of p38 MAPK activation. A strong and continuous phosphorylation of the p38 MAPK led to the overexpression of Bcl-2 after treatment in persistent cells presenting high density of CD24 on cell membrane. This phenotype enabled the cells to enter in slow-down of cell cycle, after which several weeks later, the dormant cells proliferated again. Importantly, the use of a p38 activity inhibitor sensitized cells to drug treatment and avoided chemoresistance.

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