scholarly journals Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

2021 ◽  
Vol 22 (18) ◽  
pp. 10177
Author(s):  
Susan Costantini ◽  
Francesca Capone ◽  
Andrea Polo ◽  
Palmina Bagnara ◽  
Alfredo Budillon
Keyword(s):  
Therapeutic Target ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
Protein Localization ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Cancer Cell Survival ◽  
Cancer Types ◽  
Potential Cancer

Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.

Dysregulation of HOX as a Potential Therapeutic Target in Breast Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ji-Yeon Lee ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Hox Genes ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Genome Structure ◽  
Control Cell ◽  
Three Dimensional ◽  
Cellular Processes ◽  
Hox Protein

: HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer; they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs, embedded within the HOX cluster, and the role of these molecules in breast cancer have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

2019 ◽  
Vol 20 (14) ◽  
pp. 1474-1485 ◽  
Author(s):  
Eyaldeva C. Vijayakumar ◽  
Lokesh Kumar Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Myocardial Infarction ◽  
Vagus Nerve Stimulation ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Dna Binding Protein ◽  
High Mobility Group ◽  
Eukaryotic Cells ◽  
Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

scholarly journals NFKB1 and Cancer: Friend or Foe?

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 133 ◽  
Author(s):  
Julia Concetti ◽  
Caroline L Wilson
Keyword(s):  
Immune Responses ◽  
Cancer Progression ◽  
Multiple Roles ◽  
Current Evidence ◽  
Cellular Processes ◽  
Specific Manner ◽  
Organ Specific ◽  
A Cell ◽  
Potential Cancer

Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, it is not surprising that dysregulated and chronic NF-κB signalling can have a profound impact on cellular homeostasis. Here we discuss NFKB1 (p105/p50), one of the five subunits of NF-κB, widely implicated in carcinogenesis, in some cases driving cancer progression and in others acting as a tumour-suppressor. The complexity of the role of this subunit lies in the multiple dimeric combination possibilities as well as the different interacting co-factors, which dictate whether gene transcription is activated or repressed, in a cell and organ-specific manner. This review highlights the multiple roles of NFKB1 in the development and progression of different cancers, and the considerations to make when attempting to manipulate NF-κB as a potential cancer therapy.

scholarly journals TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis

2019 ◽  
Vol 121 (12) ◽  
pp. 1069-1078 ◽  
Author(s):  
Guanghui Zhang ◽  
Qingzong Zhu ◽  
Gang Fu ◽  
Jianbing Hou ◽  
Xiaosong Hu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Biological Effect ◽  
Thyroid Hormone Receptor ◽  
E3 Ubiquitin Ligase ◽  
Mitotic Checkpoint ◽  
Migration And Invasion ◽  
Cell Models ◽  
Aaa Atpase

Abstract Background Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important role in the mitotic checkpoint. TRIP13 is highly expressed in various human tumours and promotes tumorigenesis. However, the biological effect of TRIP13 in GBM cells remains unclear. Methods We generated GBM cell models with overexpressed or silenced TRIP13 via lentivirus-mediated overexpression and RNAi methods. The biological role of TRIP13 in the proliferation, migration and invasion of GBM cells has been further explored. Results Our research indicated that TRIP13 was highly expressed in GBM tissues and cells. We found that the proliferation, migration and invasion abilities were inhibited in TRIP13-knockdown GBM cells. These results indicated that TRIP13 plays an important role in the tumorigenesis of GBM. Moreover, we found that TRIP13 first stabilised c-MYC by inhibiting the transcription of FBXW7, which is an E3 ubiquitin ligase of c-MYC, by directly binding to the promoter region of FBXW7. Therefore, our study indicated that the TRIP13/FBXW7/c-MYC pathway might provide a prospective therapeutic target in the treatment of GBM. Conclusions These results indicated that TRIP13 plays an oncogenic role in GBM. The TRIP13/FBXW7/c-MYC pathway might act as a prospective therapeutic target for GBM patients.

scholarly journals Active regulator of SIRT1 is required for cancer cell survival but not for SIRT1 activity

Open Biology ◽  
2013 ◽  
Vol 3 (11) ◽  
pp. 130130 ◽  
Author(s):  
John R. P. Knight ◽  
Simon J. Allison ◽  
Jo Milner
Keyword(s):  
Cell Survival ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Survival ◽  
Cancer Cell Lines ◽  
Cellular Processes ◽  
Disease States ◽  
Cancer Cell Survival ◽  
P53 Activation

The NAD + -dependent deacetylase SIRT1 is involved in diverse cellular processes, and has also been linked with multiple disease states. Among these, SIRT1 expression negatively correlates with cancer survival in both laboratory and clinical studies. Active regulator of SIRT1 (AROS) was the first reported post-transcriptional regulator of SIRT1 activity, enhancing SIRT1-mediated deacetylation and downregulation of the SIRT1 target p53. However, little is known regarding the role of AROS in regulation of SIRT1 during disease. Here, we report the cellular and molecular effects of RNAi-mediated AROS suppression, comparing this with the role of SIRT1 in a panel of human cell lines of both cancerous and non-cancerous origins. Unexpectedly, AROS is found to vary in its modulation of p53 acetylation according to cell context. AROS suppresses p53 acetylation only following the application of cell damaging stress, whereas SIRT1 suppresses p53 under all conditions analysed. This supplements the original characterization of AROS but indicates that SIRT1 activity can persist following suppression of AROS. We also demonstrate that knockdown of AROS induces apoptosis in three cancer cell lines, independent of p53 activation. Importantly, AROS is not required for the viability of three non-cancer cell lines indicating a putative role for AROS in specifically promoting cancer cell survival.

scholarly journals Mending a broken heart: the role of mitophagy in cardioprotection

2015 ◽  
Vol 308 (3) ◽  
pp. H183-H192 ◽  
Author(s):  
Alexandra G. Moyzis ◽  
Junichi Sadoshima ◽  
Åsa B. Gustafsson
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Cellular Processes ◽  
Differentiated Cells ◽  
Calcium Storage ◽  
Response To Stress ◽  
Metabolite Synthesis ◽  
Energy Dependent

The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation.

Vitamin D/VDR in acute kidney injury: a potential therapeutic target

2020 ◽  
Vol 27 ◽  
Author(s):  
Siqing Jiang ◽  
Lihua Huang ◽  
Wei Zhang ◽  
Hao Zhang
Keyword(s):  
Vitamin D ◽  
Acute Kidney Injury ◽  
Therapeutic Target ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Kidney Injury ◽  
Potential Therapeutic Target ◽  
Promising Therapeutic Target ◽  
Incidence And Mortality

: Despite many strategies and parameters used in clinical practice, the incidence and mortality of acute kidney injury (AKI) are still high with poor prognosis. With the development of molecular biology, the role of vitamin D and vitamin D receptor (VDR) in AKI is drawing increasing attention. Accumulated researches have suggested that Vitamin D deficiency is a risk factor of both clinical and experimental AKI, and vitamin D/VDR could be a promising therapeutic target against AKI. However, more qualitative clinical researches are needed to provide stronger evidence for clinical application of vitamin D and VDR agonists in the future. Issues like the route and dosage of administration also await more attention. The present review aims to summarize the current works on the role of vitamin D/VDR in AKI and try to provide some new insight of its therapeutic potential.

The Therapeutic Potential of miR-7 in Cancers

2019 ◽  
Vol 19 (20) ◽  
pp. 1707-1716 ◽  
Author(s):  
Miao Li ◽  
Meng Pan ◽  
Chengzhong You ◽  
Jun Dou
Keyword(s):  
Tumor Suppressor ◽  
Future Study ◽  
Therapeutic Potential ◽  
Biological Processes ◽  
Multiple Cancer ◽  
Current Review ◽  
Cancer Types ◽  
The Relationship ◽  
Potent Tumor

MiRNAs play an important role in cancers. As a potent tumor suppressor, miRNA-7(miR-7) has been demonstrated to inhibit the diverse fundamental biological processes in multiple cancer types including initiation, growth and metastasis by targeting a number of molecules and signaling pathways. This current review summarizes and discusses the relationship between miR-7 and cancers and the therapeutic potential of miR-7 in cancers. It may provide new integrative understanding for future study on the role of miR-7 in cancers.

scholarly journals The Dual Role of TAM Receptors in Autoimmune Diseases and Cancer: An Overview

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 166 ◽  
Author(s):  
Martha Wium ◽  
Juliano Paccez ◽  
Luiz Zerbini
Keyword(s):  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Tyrosine Kinases ◽  
Therapeutic Potential ◽  
Cellular Processes ◽  
Tam Receptors ◽  
Different Types ◽  
Extracellular Environment ◽  
Migration And Development

Receptor tyrosine kinases (RTKs) regulate cellular processes by converting signals from the extracellular environment to the cytoplasm and nucleus. Tyro3, Axl, and Mer (TAM) receptors form an RTK family that plays an intricate role in tissue maintenance, phagocytosis, and inflammation as well as cell proliferation, survival, migration, and development. Defects in TAM signaling are associated with numerous autoimmune diseases and different types of cancers. Here, we review the structure of TAM receptors, their ligands, and their biological functions. We discuss the role of TAM receptors and soluble circulating TAM receptors in the autoimmune diseases systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Lastly, we discuss the effect of TAM receptor deregulation in cancer and explore the therapeutic potential of TAM receptors in the treatment of diseases.

scholarly journals Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors

2015 ◽  
Vol 112 (27) ◽  
pp. 8314-8319 ◽  
Author(s):  
Francois Bordeleau ◽  
Joseph P. Califano ◽  
Yashira L. Negrón Abril ◽  
Brooke N. Mason ◽  
Danielle J. LaValley ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Alternative Splicing ◽  
Splice Variant ◽  
Sr Proteins ◽  
Matrix Stiffness ◽  
Cellular Processes ◽  
Cancer Types ◽  
Physical Tools

Alternative splicing of proteins gives rise to different isoforms that play a crucial role in regulating several cellular processes. Notably, splicing profiles are altered in several cancer types, and these profiles are believed to be involved in driving the oncogenic process. Although the importance of alternative splicing alterations occurring during cancer is increasingly appreciated, the underlying regulatory mechanisms remain poorly understood. In this study, we use both biochemical and physical tools coupled with engineered models, patient samples, and a murine model to investigate the role of the mechanical properties of the tumor microenvironment in regulating the production of the extra domain-B (EDB) splice variant of fibronectin (FN), a hallmark of tumor angiogenesis. Specifically, we show that the amount of EDB-FN produced by endothelial cells increases with matrix stiffness both in vitro and within mouse mammary tumors. Matrix stiffness regulates splicing through the activation of serine/arginine rich (SR) proteins, the splicing factors involved in the production of FN isoforms. Activation of the SR proteins by matrix stiffness and the subsequent production of EDB-FN are dependent on intracellular contractility and PI3K-AKT signaling. Notably, matrix stiffness-mediated splicing is not limited to EDB-FN, but also affects splicing in the production of PKC βII and the VEGF 165b splice variant. Together, these results demonstrate that the mechanical properties of the microenvironment regulate alternative splicing and establish a previously unidentified mechanism by which cells can adapt to their microenvironment.

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