CRHBP, a novel multiple cancer biomarker connected with better prognosis and anti-tumorigenicity.

Background: The corticotropin-releasing hormone-binding protein (CRHBP) plays a crucial role in regulating corticotropin release. Little is known about the role of CRHBP, a major regulator of neuroendocrine, autonomic, and stress adaptation, in tumors. In this study, we aimed to investigate the clinical and molecular landscapes of CRHBP in various types of tumors.

Cancer stem cells: Masters of all traits.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer.

Role of SYT11 in human pan-cancer using comprehensive approaches.

Background: Synaptotagmin 11 (SYT11) plays a pivotal role in neuronal vesicular trafficking and exocytosis. However, no independent prognostic studies have focused on various cancers. In this study, we aimed to summarize the clinical significance and molecular landscape of SYT11 in various tumor types.

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.

Unlabelled: Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses.

Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy.

Background: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing.

R-PTP-κ Inhibits Contact-Dependent Cell Growth by Suppressing E2F Activity.

Density-dependent regulation of cell growth is presumed to be caused by cell-cell contact, but the underlying molecular mechanism is not yet clearly defined. Here, we report that receptor-type protein tyrosine phosphatase-kappa (R-PTP-κ) is an important regulator of cell contact-dependent growth inhibition. R-PTP-κ expression increased in proportion to cell density.

Synaptotagmin 11 scaffolds MKK7-JNK signaling process to promote stem-like molecular subtype gastric cancer oncogenesis.

Background: Identifying biomarkers related to the diagnosis and treatment of gastric cancer (GC) has not made significant progress due to the heterogeneity of tumors. Genes involved in histological classification and genetic correlation studies are essential to develop an appropriate treatment for GC.

Methods: In vitro and in vivo lentiviral shRNA library screening was performed.

LPIN1 Induces Gefitinib Resistance in EGFR Inhibitor-Resistant Non-Small Cell Lung Cancer Cells.

Drug resistance limits the efficacy of targeted therapies, including tyrosine kinase inhibitors (TKIs); however, a substantial portion of the drug resistance mechanisms remains unexplained. In this study, we identified LPIN1 as a key factor that regulates gefitinib resistance in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) cells. Unlike TKI-sensitive HCC827 cells, gefitinib treatment induced LPIN1 expression and increased diacylglycerol concentration in TKI-resistant H1650 cells, followed by the activation of protein kinase C delta and nuclear factor kappa B (NF-κB) in an LPIN1-dependent manner, resulting in cancer cell survival.

Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers.

N-Myc downstream regulated gene 3 (NDRG3) is a unique pro-tumorigenic member among NDRG family genes, mediating growth signals. Here, we investigated the pathophysiological roles of NDRG3 in relation to cell metabolism by disrupting its functions in liver. Mice with liver-specific KO of NDRG3 (Ndrg3 LKO) exhibited glycogen storage disease (GSD) phenotypes including excessive hepatic glycogen accumulation, hypoglycemia, elevated liver triglyceride content, and several signs of liver injury.

Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart.

Cardiac contractile strength is recognised as being highly pH-sensitive, but less is known about the influence of pH on cardiac gene expression, which may become relevant in response to changes in myocardial metabolism or vascularization during development or disease. We sought evidence for pH-responsive cardiac genes, and a physiological context for this form of transcriptional regulation. pHLIP, a peptide-based reporter of acidity, revealed a non-uniform pH landscape in early-postnatal myocardium, dissipating in later life.

PKM2 Regulates HSP90-Mediated Stability of the IGF-1R Precursor Protein and Promotes Cancer Cell Survival during Hypoxia.

Insulin-like growth factor-1 receptor (IGF-1R), an important factor in promoting cancer cell growth and survival, is commonly upregulated in cancer cells. However, amplification of the gene is extremely rare in tumors. Here, we have provided insights into the mechanisms underlying the regulation of IGF-1R protein expression.

Targeting HSF1 as a Therapeutic Strategy for Multiple Mechanisms of EGFR Inhibitor Resistance in EGFR Mutant Non-Small-Cell Lung Cancer.

Although EGFR-TKI treatment of NSCLC (non-small-cell lung cancer) patients often achieves profound initial responses, the efficacy is transient due to acquired resistance. Multiple receptor tyrosine kinase (RTK) pathways contribute to the resistance of NSCLC to first- and third-generation EGFR-TKIs, such as erlotinib and osimertinib. To identify potential targets for overcoming EGFR-TKI resistance, we performed a gene expression signature-based strategy using connectivity map (CMap) analysis.

Subtle Role for Adenylate Kinase 1 in Maintaining Normal Basal Contractile Function and Metabolism in the Murine Heart.

Aims: Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury.

Methods And Results: Cardiac-specific AK1 overexpressing mice (AK1-OE) had 31% higher AK1 activity ( = 0.

Breaking the cycle: Targeting of NDRG1 to inhibit bi-directional oncogenic cross-talk between pancreatic cancer and stroma.

Pancreatic cancer (PaCa) is characterized by dense stroma that hinders treatment efficacy, with pancreatic stellate cells (PSCs) being a major contributor to this stromal barrier and PaCa progression. Activated PSCs release hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-1) that induce PaCa proliferation, metastasis and resistance to chemotherapy. We demonstrate for the first time that the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is a potent inhibitor of the PaCa-PSC cross-talk, leading to inhibition of HGF and IGF-1 signaling.

Cardiac Complications of Propionic and Other Inherited Organic Acidemias.

Clinical observations and experimental studies have determined that systemic acid-base disturbances can profoundly affect the heart. A wealth of information is available on the effects of altered pH on cardiac function but, by comparison, much less is known about the actions of the organic anions that accumulate alongside H ions in acidosis. In the blood and other body fluids, these organic chemical species can collectively reach concentrations of several millimolar in severe metabolic acidoses, as in the case of inherited organic acidemias, and exert powerful biological actions on the heart that are not intuitive to predict.

Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart.

Aims: Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i).

The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity.

The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.

The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents.

Background: The c-MET oncoprotein drives cancer progression in a variety of tumors through its signaling transduction pathways. This oncoprotein is also degraded by multiple mechanisms involving the lysosome, proteasome and cleavage by proteases. Targeting c-MET degradation pathways may result in effective therapeutic strategies.

Resveratrol Inhibits Particulate Matter-Induced Inflammatory Responses in Human Keratinocytes.

Particulate matter (PM), a major air pollutant, is a complex mixture of solid and liquid particles of various sizes. PM has been demonstrated to cause intracellular inflammation in human keratinocytes, and is associated with various skin disorders, including atopic dermatitis, eczema, and skin aging. Resveratrol is a natural polyphenol with strong antioxidant properties, and its beneficial effects against skin changes due to PM remain elusive.

NDRG1 suppresses basal and hypoxia-induced autophagy at both the initiation and degradation stages and sensitizes pancreatic cancer cells to lysosomal membrane permeabilization.

Background: N-myc downstream regulated gene 1 (NDRG1) is an established stress-response protein. This study investigated the effects of NDRG1 on autophagic degradation and how this can be therapeutically exploited.

Methods: Cell culture, western analysis, confocal microscopy, acridine orange staining, cholesterol determination, cellular proliferation assessment and combination index (CI) estimation.

Overcoming tamoxifen resistance in oestrogen receptor-positive breast cancer using the novel thiosemicarbazone anti-cancer agent, DpC.

Background And Purpose: Breast cancer is the leading cause of death in women worldwide, with resistance to current therapeutic strategies, including tamoxifen, causing major clinical challenges and leading to more aggressive and metastatic disease. To address this, novel strategies that can inhibit the mechanisms responsible for tamoxifen resistance need to be assessed.

Experimental Approach: We examined the effect of the novel, clinically-trialled, thiosemicarbazone anti-cancer agent, DpC, and its potential as a combination therapy with the clinically used estrogen receptor (ER) antagonist, tamoxifen, using both tamoxifen-resistant and -sensitive, human breast cancer cells (MDA-MB-453, MDA-MB-231 and MCF-7) in 2D and 3D cell-culture.