Ion channels (IChs) are transmembrane proteins that selectively drive ions across membranes. The function of IChs partially relies on their abundance and proper location in the cell, fine-tuned by the delicate balance between secretory, endocytic, and degradative pathways. The disruption of this balance is associated with several diseases, such as Liddle’s and long QT syndromes. Because of the vital role of these proteins in human health and disease, knowledge of ICh turnover is essential. Clathrin-dependent and -independent mechanisms have been the primary mechanisms identified with ICh endocytosis and degradation. Several molecular determinants recognized by the cellular internalization machinery have been discovered. Moreover, specific conditions can trigger the endocytosis of many IChs, such as the activation of certain receptors, hypokalemia, and some drugs. Ligand-dependent receptor activation primarily results in the posttranslational modification of IChs and the recruitment of important mediators, such as β-arrestins and ubiquitin ligases. However, endocytosis is not a final fate. Once internalized into endosomes, IChs are either sorted to lysosomes for degradation or recycled back to the plasma membrane. Rab proteins are crucial participants during these turnover steps. In this review, we describe the major ICh endocytic pathways, the signaling inputs triggering ICh internalization, and the key mediators of this essential cellular process.
The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. The regulatory subunit KCNE4 acts as an ancillary peptide of Kv1.3, modulates K+ currents and controls channel abundance at the cell surface. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Thus, KCNE4 is crucial for Ca2+-dependent Kv1.3-related leukocyte functions. To better understand the role of KCNE4 in the regulation of the immune system, we manipulated its expression in various leukocyte cell lines. Jurkat T lymphocytes exhibit low KCNE4 levels, whereas CY15 dendritic cells, a model of professional antigen-presenting cells, robustly express KCNE4. When the cellular KCNE4 abundance was increased in T cells, the interaction between KCNE4 and Kv1.3 affected important T cell physiological features, such as channel rearrangement in the immunological synapse, cell growth, apoptosis and activation, as indicated by decreased IL-2 production. Conversely, ablation of KCNE4 in dendritic cells augmented proliferation. Furthermore, the LPS-dependent activation of CY15 cells, which induced Kv1.3 but not KCNE4, increased the Kv1.3-KCNE4 ratio and increased the expression of free Kv1.3 without KCNE4 interaction. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions.
9059 Background: ABTL0812 induces the inhibition of Akt/mTOR pathway by upregulation of TRIB3 protein, an endogenous Akt inhibitor, and promotes endoplasmic reticulum (ER) stress. As a result, ABTL0812 induces cytotoxic autophagy that leads to specific death of cancer cells, without affecting non-tumor cell viability. A Phase II clinical trial was designed where ABTL0812 was evaluated in combination with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung cancer (NSCLC). Methods: ABTL0812 was administered 1300 mg TID orally with 175 mg/m2 paclitaxel and AUC5 carboplatin every 3 weeks, for up to 8 cycles, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients with non-irradiable IIIb stage or stage IV squamous NSCLC. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety and tolerability according to CTCAE v4.03, pharmacokinetics (PK) of ABTL0812 enantiomers ((-)-ABTL and (+)-ABTL) and pharmacodynamics assessed by two surrogate blood biomarkers: TRIB3 and CHOP. Results: Forty patients were included; median age was 66.1 years old; 90% men/10% women; 100% ECOG 0-1; 30% current smokers/67.5% former smokers and 37.5% had received prior chemotherapy > 12 months before inclusion. 39 patients had at least 1 adverse event (AE), anemia appeared in 32.5% of the patients (5.0% grade 3), neutropenia in 27.5% (25% grades 3-4) and thrombocytopenia in 17.5% of the patients (2.5% grade 3). For non-hematological AEs, asthenia was reported in 62.5% of the patients (2.5% grade 3); diarrhea in 45% (no grade 3-4) and nausea in 37.5% (5% grades 3-4). Twenty-five patients reach the primary endpoint for efficacy evaluation. ORR was 52.0% (95% CI 34.2-65.9) and 32.0% of the patients had stable disease. Median OS was 22.5 months (10.4-NC), median progression free survival 6.2 months (4.4-8.8), and DOR 5.1 months (3.9-7.4). Area under the curve (µg·h/ml) for (-)-ABTL and (+)-ABTL were 39.0±12.3 and 17.1±6.3 respectively, maximal concentrations (µg/ml) were 6.4±2.6 and 5.1±2.2 and minimum concentrations (µg/ml) 2.2±1.5 and 0.8±1.3. TRIB3 and CHOP PD biomarkers were induced by the treatment. Conclusions: The combination of ABTL0812 with paclitaxel and carboplatin shows survival outcomes that compare favorably with historical controls in squamous-NSCLC with an acceptable safety profile. PK analysis is compatible with drug activity, and pharmacodynamic analysis shows drug engagement. Clinical trial information: NCT03366480 .
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