Pitstop-2 and its novel derivative RVD-127 disrupt global cell dynamics and nuclear pores integrity by direct interaction with small GTPases.

Clathrin-mediated endocytosis (CME) is an essential cell physiological process of broad biomedical relevance. Since the recent introduction of Pitstop-2 as a potent CME inhibitor, we and others have reported on substantial clathrin-independent inhibitory effects. Herein, we developed and experimentally validated a novel fluorescent derivative of Pitstop-2, termed RVD-127, to clarify Pitstop-2 diverse effects.

Imaging of the calcium activated potassium channel 3.1 (K 3.1) in vivo using a senicapoc-derived positron emission tomography tracer.

The calcium-activated potassium channel 3.1 (K 3.1) is overexpressed in many tumor entities and has predictive power concerning disease progression and outcome.

Functional expression of mitochondrial K3.1 channels in non-small cell lung cancer cells.

Lung cancer is one of the leading causes of cancer-related deaths worldwide. The Ca-activated K channel K3.1 contributes to the progression of non-small cell lung cancer (NSCLC).

TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination.

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies.

Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K3.1) channels .

Expression of the Ca activated potassium channel 3.1 (K3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival.

Impact of the Nuclear Envelope on Malignant Transformation, Motility, and Survival of Lung Cancer Cells.

Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell-physiological processes. It is hypothesized that NPCs are critical for malignant transformation and survival of lung cancer cells, and test the hypothesis in lowly and highly metastatic non-small human lung cancer cells (NSCLCs). It is shown that malignant transformation is paralleled by an increased NPCs density, and a balanced pathological weakening of the physiological stringency of the NPC barrier.

K channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549).

Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs.

Co-staining of K 3.1 Channels in NSCLC Cells with a Small-Molecule Fluorescent Probe and Antibody-Based Indirect Immunofluorescence.

The Ca activated potassium channel 3.1 (K 3.1) is involved in critical steps of the metastatic cascade, such as proliferation, migration, invasion and extravasation.

Role of the Intracellular Sodium Homeostasis in Chemotaxis of Activated Murine Neutrophils.

The importance of the intracellular Ca concentration ([Ca]) in neutrophil function has been intensely studied. However, the role of the intracellular Na concentration ([Na]) which is closely linked to the intracellular Ca regulation has been largely overlooked. The [Na] is regulated by Na transport proteins such as the Na/Ca-exchanger (NCX1), Na/K-ATPase, and Na-permeable, transient receptor potential melastatin 2 (TRPM2) channel.

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology.

Tissue acidosis plays a pivotal role in tumor progression: in particular, interstitial acidosis promotes tumor cell invasion, and is a major contributor to the dysregulation of tumor immunity and tumor stromal cells. The cell membrane and integral membrane proteins commonly act as important sensors and transducers of altered pH. Cell adhesion molecules and cation channels are prominent membrane proteins, the majority of which is regulated by protons.

Ion Channels in Lung Cancer.

Ion channels are a major class of membrane proteins that play central roles in signaling within and among cells, as well as in the coupling of extracellular events with cellular responses. Dysregulated ion channel activity plays a causative role in many diseases including cancer. Here, we will review their role in lung cancer.

Mechanosensitive ion channels push cancer progression.

In many cases, the mechanical properties of a tumor are different from those of the host tissue. Mechanical cues regulate cancer development by affecting both tumor cells and their microenvironment, by altering cell migration, proliferation, extracellular matrix remodeling and metastatic spread. Cancer cells sense mechanical stimuli such as tissue stiffness, shear stress, tissue pressure of the extracellular space (outside-in mechanosensation).

The Role of TRP Channels in the Metastatic Cascade.

A dysregulated cellular Ca homeostasis is involved in multiple pathologies including cancer. Changes in Ca signaling caused by altered fluxes through ion channels and transporters (the transportome) are involved in all steps of the metastatic cascade. Cancer cells thereby "re-program" and "misuse" the cellular transportome to regulate proliferation, apoptosis, metabolism, growth factor signaling, migration and invasion.

The function of TRP channels in neutrophil granulocytes.

Neutrophil granulocytes are exposed to widely varying microenvironmental conditions when pursuing their physiological or pathophysiological functions such as fighting invading bacteria or infiltrating cancer tissue. Examples for harsh environmental challenges include among others mechanical shear stress during the recruitment from the vasculature or the hypoxic and acidotic conditions within the tumor microenvironment. Chemokine gradients, reactive oxygen species, pressure, matrix elasticity, and temperature can be added to the list of potential challenges.

K3.1 channel inhibition leads to an ICAM-1 dependent increase of cell-cell adhesion between A549 lung cancer and HMEC-1 endothelial cells.

Early metastasis leads to poor prognosis of lung cancer patients, whose 5-year survival rate is only 15%. We could recently show that the Ca sensitive K channel K3.1 promotes aggressive behavior of non-small cell lung cancer (NSCLC) cells and that it can serve as a prognostic marker in NSCLC.

Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.

Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.

Mutations of the EPHB6 receptor tyrosine kinase induce a pro-metastatic phenotype in non-small cell lung cancer.

Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer.

The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth.

Introduction: The functions of large noncoding RNAs (ncRNAs) have remained elusive in many cases. Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) is an ncRNA that is highly expressed in several tumor types.

Methods: Overexpression and RNA interference (RNAi) approaches were used for the analysis of the biological functions of MALAT-1 RNA.

AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.

The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self-renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target.

Chemotaxis of MDCK-F cells toward fibroblast growth factor-2 depends on transient receptor potential canonical channel 1.

Movement toward the source of a chemoattractant gradient is a basic cellular property in health and disease. Enhanced migration during metastasis involves deregulated growth factor signaling. Growth factor stimulation and cell migration converge both on the important second messenger Ca(2+).

The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer.

Purpose: Loss of EPHB6 receptor tyrosine kinase expression in early-stage non-small cell lung carcinoma (NSCLC) is associated with the subsequent development of distant metastasis. Here, we analyzed the regulation and function of EPHB6 in lung cancer metastasis.

Experimental Design: The expression levels of EPHB6 were compared among normal lung tissue (n = 9), NSCLC without metastasis (n = 39), and NSCLC with metastasis (n = 39) according to the history of the patients.

The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma.

Decreased expression levels of EPHB6, a member of the receptor tyrosine kinases (RTKs), are associated with an increased risk of metastasis development in early stage non-small cell lung cancer (NSCLC). However, the signaling properties of the kinase-defective EPHB6 receptor are not well-understood. Here, we show that expression of EPHB6 in A549 lung adenocarcinoma cells led to phosphorylation of the MAP kinase ERK.

S100A2 induces metastasis in non-small cell lung cancer.

Purpose: S100 proteins are implicated in metastasis development in several cancers. In this study, we analyzed the prognostic role of mRNA levels of all S100 proteins in early stage non-small cell lung cancer (NSCLC) patients as well as the pathogenetic of S100A2 in the development of metastasis in NSCLC.

Experimental Design: Microarray data from a large NSCLC patient cohort was analyzed for the prognostic role of S100 proteins for survival in surgically resected NSCLC.

Adjuvant therapy with small hairpin RNA interference prevents non-small cell lung cancer metastasis development in mice.

Development of distant metastasis is the major reason for cancer-related deaths worldwide. Adjuvant therapy approaches after local therapies are most effective when specific targets are inhibited. Recently, we identified S100P overexpression as a strong predictor for metastasis development in early-stage non-small cell lung cancer (NSCLC) patients.