scholarly journals Identification of a Posttranslational Mechanism for the Regulation of hERG1 K+ Channel Expression and hERG1 Current Density in Tumor Cells

2008 ◽  
Vol 28 (16) ◽  
pp. 5043-5060 ◽  
Author(s):  
Leonardo Guasti ◽  
Olivia Crociani ◽  
Elisa Redaelli ◽  
Serena Pillozzi ◽  
Simone Polvani ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Neuroblastoma Cells ◽  
Surface Expression ◽  
K Channel ◽  
Aberrant Expression ◽  
Channel Surface ◽  
Channel Expression ◽  
Herg1 Channel

ABSTRACT A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K+ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (IhERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher IhERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

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.

scholarly journals CXCL5 Downregulation in Villous Tissue Is Correlated With Recurrent Spontaneous Abortion

2021 ◽  
Vol 12 ◽  
Author(s):  
Sainan Zhang ◽  
Jinli Ding ◽  
Jiayu Wang ◽  
Tailang Yin ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Spontaneous Abortion ◽  
Molecular Mechanisms ◽  
Recurrent Spontaneous Abortion ◽  
Trophoblast Invasion ◽  
Trophoblast Cells ◽  
Childbearing Age ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Villous Tissue

Recurrent spontaneous abortion (RSA) affects 5% of childbearing-age women worldwide. Inadequate trophoblast invasion is one of the main reasons for the development of RSA; however, the underlying molecular mechanisms for RSA have not been fully understood, and further explanation is urgently needed. C-X-C motif chemokine ligand 5 (CXCL5) is reported to contribute to the invasion of cancer cells, and its aberrant expression is associated with the cellular process of tumor pathology. Considering the high behavioral similarity between trophoblast cells and cancer cells, we hypothesized that CXCL5 may influence trophoblast invasion, and its expression levels in villous tissue may be correlated with RSA. In this study, we firstly investigated the CXCL5 expression in placental villous tissues of 15 RSA patients and 13 control patients, and the results showed that CXCL5 levels were significantly lower in villous tissue from RSA patients than those of the controls. Further in vitro experiments presented that recombinant human CXCL5 can enhance trophoblast migration, invasion, and epithelial-to-mesenchymal transition (EMT) process. We also demonstrated that CXCL5 exerted these effects on trophoblast cells through PI3K/AKT/ERK1/2 signaling pathway. In conclusion, these data indicate that CXCL5 downregulation in human villous tissue is correlated with RSA. Additionally, we found that estrogen, progesterone, human chorionic gonadotropin, and decidual stromal cells can regulate CXCL5 and chemokine receptor 2 (CXCR2) expression of trophoblast in a cell manner.

scholarly journals FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3110 ◽  
Author(s):  
Dinh-Chuong Pham ◽  
Yu-Chuan Chang ◽  
Shian-Ren Lin ◽  
Yuh-Ming Fuh ◽  
May-Jywan Tsai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Neuroblastoma Cells ◽  
Beclin 1 ◽  
Potential Candidate ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Anti Cancer

Human neuroblastoma cancer is the most typical extracranial solid tumor. Yet, new remedial treatment therapies are demanded to overcome its sluggish survival rate. Neferine, isolated from the lotus embryos, inhibits the proliferation of various cancer cells. This study aimed to evaluate the anti-cancer activity of neferine in IMR32 human neuroblastoma cells and to expose the concealable molecular mechanisms. IMR32 cells were treated with different concentrations of neferine, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability. In an effort to determine the molecular mechanisms in neferine-incubated IMR32 cells, cell cycle arrest, cell migration, and focal adhesion kinase (FAK), the 70-kDa ribosomal S6 kinase 1 (S6K1), poly (ADP-ribose) polymerase (PARP), caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3 (LC3) protein expressions were investigated. Neferine strongly disrupted the neuroblastoma cell growth via induction of G2/M phase arrest. Furthermore, neferine provoked autophagy and apoptosis in IMR32 cells, confirmed by p-FAK, and p-S6K1 reduction, LC3-II accumulation, Beclin-1 overexpression, and cleaved caspase-3/PARP improvement. Finally, neferine markedly retarded cell migration of neuroblastoma cancer cells. As a result, our findings for the first time showed an explicit anti-cancer effect of neferine in IMR32 cells, suggesting that neferine might be a potential candidate against human neuroblastoma cells to improve clinical outcomes with further in vivo investigation.

scholarly journals Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1085
Author(s):  
Nikolay Mehterov ◽  
Maria Kazakova ◽  
Yordan Sbirkov ◽  
Boyan Vladimirov ◽  
Nikolay Belev ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Chemotherapeutic Agents ◽  
Human Genes ◽  
Splicing Variants ◽  
Almost All ◽  
Aberrant Rna

Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.

scholarly journals The Effects of CD82 Palmitoylation on the Metabolic Pathways of EGFR and c-Met in Breast Cancer Cells and their Molecular Mechanisms

2021 ◽  
Author(s):  
Jingya Bu ◽  
Weiliang Zhong ◽  
Meixian Li ◽  
Shuiqing He ◽  
Mingzhe Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Metabolic Pathways ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Metastasis Suppressor ◽  
Recycling Endosome ◽  
Palmitoylation Site

Abstract Background: As a tumor metastasis suppressor, tetraspanin CD82 is reduced in many malignant tumors and often affects the composition of tumor microenvironment by changing the heterogeneity of cell membrane. EGFR or c-Met signaling pathway can regulate the metastasis ability of tumor cells and participate in the formation of tetraspanin web. The study of CD82 palmitoylation modification and metabolic pathway of tumor related molecules in tumor cells is still incomplete. This article focuses on studying the expression and distribution of EGFR and c-Met in cancer cells as well as related metabolic pathways and their molecular mechanisms after studying different palmitoylation site mutations.Methods: Western blot and immunofluorescence methods were used to detect the distribution of EGFR in breast cancer MDA-MB-231 cells after different CD82 palmitoylation site mutations. Then use the immunoprecipitation method to determine the interaction relationship between the molecules and the molecular mechanism.Results: We found that when CD82 combined with palmitoylation mutation at Cys5+Cys74 can enhance the internalization of EGFR, but has no effect on the expression and location of c-Met. When CD82 is combined with palmitoylation mutation at the Cys5+Cys74 site, with the assistance of tubulin, EGFR is internalized and strengthened by direct binding to CD82 and a large number of localizations on the recycling endosome. By forming the EGFR/CD82/Rab11a/FIP2 complex, it is metabolized through the circulation pathway, and re-expression of EGFR and CD82 on the cell membrane.Conclusions: From our results, we can demonatrate that CD82 palmitoylation mutation can change the distribution of EGFR in breast cancer cells, which may provide new ideas for breast cancer treatment.

scholarly journals Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

2017 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Marcelo Boareto ◽  
Bisrat G Debeb ◽  
Nicola Aceto ◽  
Mary C Farach-Carson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Inflammatory Breast Cancer ◽  
Intercellular Communication ◽  
Primary Tumor ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Cluster Formation ◽  
Metastatic Potential

AbstractMetastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells (CTCs) shed off from the primary tumor. In circulation, CTCs are found both as single cells and as clusters of cells. The clusters of CTCs, although many fewer in number, possess much higher metastatic potential as compared to that of individual CTCs. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters - (a) hybrid epithelial/mesenchymal (E/M) phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer (IBC) as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms.

Expression and signaling of Toll-like receptor 4 (TLR4) and MyD88 in ovarian carcinoma cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16508-e16508 ◽  
Author(s):  
M. E. Szajnik ◽  
M. J. Szczepanski ◽  
M. Czystowska ◽  
E. Elishaev ◽  
M. Mandapathil ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Carcinoma ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Human Cancer ◽  
Progression Free Survival

e16508 Background: TLR4, expressed by the cells of the immune system play a role in the protection of the host against pathogens. TLRs are also expressed on human cancer cells, but their role in tumor growth is unknown. The aim of this study was to correlate the presence of TLR4 and MyD88 expression with clinicopathologic outcome in patients with ovarian cancer and to analyze the consequences of signaling via the TLR4/MyD88 pathway in ovarian cancer cell lines. Methods: Tumor specimens from 41 patients with ovarian carcinoma were evaluated for TLR4 and MyD88 by immunohistochemistry and correlated with clinical and pathologic disease features. TLR4/MyD88 expression in OVCAR3, SKOV3, and A2780 was determined using RT-PCR, WB, and immunohistochemistry. NF-kB translocation to nucleus was measured by confocal microscopy. Culture supernatants were tested for levels of cytokines in Luminex-based assays. Proliferation of cancer cells was measured in the CFSE assays. Their sensitivity to paclitaxel (PLX) was measured by Annexin V binding. Western Blot analysis was used to measure activation of the PI3K/Akt, IRAK 1, IRAK 4, and TRIF. Results: In ovarian cancer patients TLR4 and MyD88 expression by the tumor was observed in 100% and 83% of tissues, respectively. The expression of MyD88 was associated with shorter progression-free survival (42 vs 31 months, p < 0.05). Ex vivo studies showed that TLR4 was expressed on OVCAR3, SKOV3, and A2780 cell lines, while A2780 did not expressed MyD88. In MyD88+ tumor cells, LPS increased proliferation (PI 17 vs 8, p < 0.05), activated NF-kB pathway and promoted cytokine production (IL-8, IL-6, RANTES, VEGF and MCP-1). LPS and PLX binding to TLR4 on MyD88+ cells induced activation of PI3K/Akt, IRAK4, and IRAK1, but decreased expression of pro-apoptotic TRIF. In contrast, in MyD88(-) cells LPS did not induce proliferation and neither LPS nor PLX induced secretion of pro-inflammatory cytokines. Further, no changes were noted in IRAK1 expression, but strong signal was observed for TRIF. TLR4+/MyD88+ tumor cells showed grater resistance to PLX. Conclusions: Our ex vivo studies elucidate the molecular mechanisms involved in TLR4/MyD88 signaling. Ligation via TLR4 leads to tumor growth, release of proinflammatory cytokines and induction of resistance to PLX-induced apoptosis. No significant financial relationships to disclose.

scholarly journals Hypoxic exosomes orchestrate tumorigenesis: molecular mechanisms and therapeutic implications

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Reza Jafari ◽  
Reza Rahbarghazi ◽  
Mahdi Ahmadi ◽  
Mehdi Hassanpour ◽  
Jafar Rezaie
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Hypoxic Condition ◽  
Rab Gtpases ◽  
Therapeutic Implications ◽  
Hypoxic Conditions ◽  
Therapeutic Opportunity ◽  
Hypoxic Tumor

AbstractThe solid tumor microenvironment possesses a hypoxic condition, which promotes aggressiveness and resistance to therapies. Hypoxic tumor cells undergo broadly metabolic and molecular adaptations and communicate with surrounding cells to provide conditions promising for their homeostasis and metastasis. Extracellular vesicles such as exosomes originating from the endosomal pathway carry different types of biomolecules such as nucleic acids, proteins, and lipids; participate in cell-to-cell communication. The exposure of cancer cells to hypoxic conditions, not only, increases exosomes biogenesis and secretion but also alters exosomes cargo. Under the hypoxic condition, different signaling pathways such as HIFs, Rab-GTPases, NF-κB, and tetraspanin are involved in the exosomes biogenesis. Hypoxic tumor cells release exosomes that induce tumorigenesis through promoting metastasis, angiogenesis, and modulating immune responses. Exosomes from hypoxic tumor cells hold great potential for clinical application and cancer diagnosis. Besides, targeting the biogenesis of these exosomes may be a therapeutic opportunity for reducing tumorigenesis. Exosomes can serve as a drug delivery system transferring therapeutic compounds to cancer cells. Understanding the detailed mechanisms involved in biogenesis and functions of exosomes under hypoxic conditions may help to develop effective therapies against cancer.

scholarly journals THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy

2021 ◽  
Vol 9 (8) ◽  
pp. e002443
Author(s):  
Chushu Li ◽  
Hao Chi ◽  
Shouyan Deng ◽  
Huanbin Wang ◽  
Han Yao ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Tissue Microarrays ◽  
Mouse Tumor ◽  
Tissue Samples ◽  
Cargo Protein ◽  
Promising Target

BackgroundThe abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.MethodsCombined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.ResultsTHADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.ConclusionsOur data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.

Sign in / Sign up

Export Citation Format

Share Document