scholarly journals Targeting Kca3.1 Channels in Cancer

2021 ◽  
Vol 55 (S3) ◽  
pp. 131-144
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Inhibitor Binding ◽  
Aggressive Cancer ◽  
Imaging Probes ◽  
Attractive Therapeutic Target ◽  
Characteristic Features ◽  
Dynamics Simulations

The Kca3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca2+ concentration. These K+ channels are widely expressed in many organs and involved in many pathologies. In particular, Kca3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of Kca3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of Kca3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using Kca3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to Kca3.1 channels in order to provide a deeper understanding of Kca3.1 channel pharmacology. Alltogether, Kca3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients.

scholarly journals Role of the NUDT Enzymes in Breast Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2267
Author(s):  
Roni H. G. Wright ◽  
Miguel Beato
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Breast Cancers ◽  
Metastatic Colonization ◽  
Hormone Receptor Positive ◽  
Aggressive Cancer ◽  
Cancer Types ◽  
Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

scholarly journals Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity

2021 ◽  
Vol 22 (2) ◽  
pp. 540
Author(s):  
Mariam Markouli ◽  
Dimitrios Strepkos ◽  
Kostas A. Papavassiliou ◽  
Athanasios G. Papavassiliou ◽  
Christina Piperi
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Integration Site ◽  
Survival Rates ◽  
Family Members ◽  
Therapy Resistance ◽  
Cellular Functions ◽  
Cns Neoplasms ◽  
Development Regulation

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

scholarly journals Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 482 ◽  
Author(s):  
Zoe Price ◽  
Noor Lokman ◽  
Carmela Ricciardelli
Keyword(s):  
Molecular Weight ◽  
Tyrosine Kinase ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Therapy Resistance ◽  
Cell Behavior ◽  
Mesenchymal Transition

Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.

scholarly journals SGK1 in Human Cancer: Emerging Roles and Mechanisms

2021 ◽  
Vol 10 ◽  
Author(s):  
Yiwen Sang ◽  
Piaoping Kong ◽  
Shizhen Zhang ◽  
Lingyu Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Kinase Activity ◽  
Human Cancer ◽  
Therapy Resistance ◽  
Cancer Cell Proliferation ◽  
Serine Threonine Kinase ◽  
Aberrant Expression ◽  
Threonine Kinase ◽  
Cancer Types

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

scholarly journals The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4720
Author(s):  
Paris Jabeen Asif ◽  
Ciro Longobardi ◽  
Michael Hahne ◽  
Jan Paul Medema
Keyword(s):  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cancer Invasion ◽  
Cancer Associated Fibroblasts ◽  
Targeted Therapeutics ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Future Studies

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.

scholarly journals Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States

2021 ◽  
Vol 10 (11) ◽  
pp. 2403
Author(s):  
Laura Bornes ◽  
Guillaume Belthier ◽  
Jacco van Rheenen
Keyword(s):  
Wound Healing ◽  
Cell Adhesion ◽  
Basement Membrane ◽  
Cell Polarity ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Mesenchymal Transition

Epithelial-to-mesenchymal transition (EMT) is a cellular program which leads to cells losing epithelial features, including cell polarity, cell–cell adhesion and attachment to the basement membrane, while gaining mesenchymal characteristics, such as invasive properties and stemness. This program is involved in embryogenesis, wound healing and cancer progression. Over the years, the role of EMT in cancer progression has been heavily debated, and the requirement of this process in metastasis even has been disputed. In this review, we discuss previous discrepancies in the light of recent findings on EMT, plasticity and hybrid E/M states. Moreover, we highlight various tumor microenvironmental cues and cell intrinsic signaling pathways that induce and sustain EMT programs, plasticity and hybrid E/M states. Lastly, we discuss how recent findings on plasticity, especially on those that enable cells to switch between hybrid E/M states, have changed our understanding on the role of EMT in cancer metastasis, stemness and therapy resistance.

scholarly journals Contrast effects of autophagy in the treatment of bladder cancer

2020 ◽  
pp. 153537022095933
Author(s):  
Ece Konac ◽  
Yener Kurman ◽  
Sümer Baltaci
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Dual Role ◽  
Cancer Treatments ◽  
Chemotherapy Drugs ◽  
Anti Cancer

Bladder cancer is a disease that negatively affects patients’ quality of life, but treatment options have remained unchanged for a long time. Although promising results have been achieved with current bladder cancer treatments, cancer recurrence, progression, and therapy resistance are the most severe problems preventing the efficiency of bladder cancer treatments. Autophagy refers to an evolutionarily conserved catabolic process in which proteins, damaged organelles, and cytoplasmic components are degraded by lysosomal enzymes. Autophagy regulates the therapeutic response to the chemotherapy drugs, thus determining the effect of therapy on cancer cells. Autophagy is a stress-induced cell survival mechanism and its excessive stimulation can cause resistance of tumor cells to therapeutic agents. Depending on the conditions, an increase in autophagy may cause treatment resistance or autophagic cell death, and it is related to important anti-cancer mechanisms, such as apoptosis. Therefore, understanding the roles of autophagy under different conditions is important for designing effective anti-cancer agents. The dual role of autophagy in cancer has attracted considerable attention in respect of bladder cancer treatment. In this review, we summarize the basic characteristics of autophagy, including its mechanisms, regulation, and functions, and we present examples from current studies concerning the dual role of autophagy in bladder cancer progression and therapy. Impact statement Autophagy acts as an intracellular recycling system. Infection and mitochondrial damage, maintaining cellular homeostasis, orchestrating nutrient stress, hypoxia, and oxidative stress are some of the physiological roles associated with autophagy. Autophagy has also context-dependent roles in cancer. Autophagy has a significant impact on tumor initiation and promotion, with both tumor-suppressive and tumor-promoting roles. Unfortunately, conventional systemic chemotherapy for cancer therapy has been reported to have primary limitations such as chemo-resistance of targeted cells. The cytoprotective role of autophagy has been postulated as one of the causes of this resistance. Hence, combination therapy using autophagy inhibitors has recently started to emerge as a noteworthy strategy in the treatment of cancer. Therefore, targeting the autophagy pathways may be a potential therapeutic strategy for addressing cancer progression or therapy resistance in the near future. This review will provide a novel insight to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion.

scholarly journals Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 374 ◽  
Author(s):  
Matthew G. K. Benesch ◽  
Xiaoyun Tang ◽  
David N. Brindley
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Cancer Field ◽  
Radiation Induced

After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.

scholarly journals The Implication of Autophagy in Gastric Cancer Progression

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1304
Author(s):  
Evangelos Koustas ◽  
Eleni-Myrto Trifylli ◽  
Panagiotis Sarantis ◽  
Nikolaos I. Kontolatis ◽  
Christos Damaskos ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Tumor Promoter ◽  
Molecular Characteristics ◽  
Gastric Cancer Patients

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.

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