Ginsenoside Compound K Promotes Proliferation, Migration and Differentiation of Schwann Cells via the Activation of MEK/ERK1/2 and PI3K/AKT Pathways.

The proliferation and differentiation of Schwann cells are critical for the remyelination of injured peripheral nerve. Ginsenoside compound K (CK) is a metabolite produced from ginsenoside Rb1 which has strong anti-inflammatory effects. However, the potential effects of CK on Schwann cells have not been studied systematically before. Therefore, this study was aimed to explore the functions of CK in Schwann cell proliferation, migration and differentiation and its potential regulatory mechanism. Primary Schwann cells and RSC96 cells were treated with or without CK at different doses. The proliferation and migration of primary Schwann cells and RSC96 cells were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The mRNA expression of myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) was tested by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of all proteins were examined by Western blot. CK could promote cell proliferation, migration and induce MAG and MBP expression in primary Schwann cells and RSC96 cells. Furthermore, CK activated MEK/ERK1/2 and PI3K/AKT pathways, and the beneficial effects of CK on primary Schwann cells and RSC96 cells were distinctly suppressed by inhibitor PD98059 or LY294002. Ginsenoside compound K induced cell proliferation, migration and differentiation via the activation of MEK/ERK1/2 and PI3K/AKT pathways in cultured primary Schwann cells and RSC96 cells.

Effects of glycyrrhizin on the pharmacokinetics of nobiletin in rats and its potential mechanism.

Context: Both nobiletin (NBL) and glycyrrhizin (GL) have anti-inflammatory and antitumor properties. These agents may be co-administered in the clinic. However, the drug-drug interaction between them is not clear.Objective: The drug-drug interaction between GL and NBL was investigated, to clarify the effect of GL on the pharmacokinetics of NBL, and its main mechanism.Materials and methods: The pharmacokinetic profiles of oral administration of NBL (50 mg/kg) in Sprague-Dawley rats of two groups with six each, with or without pre-treatment of GL (100 mg/kg/day for 7 days), were investigated. The effects of GL on the metabolic stability and transport of NBL were also investigated through the rat liver microsome and Caco-2 cell transwell models.Results: The results showed that GL significantly decreased the peak plasma concentration (from 1.74 ± 0.15 to 1.12 ± 0.10 µg/mL) and the t1/2 (7.44 ± 0.65 vs. 5.92 ± 0.68) of NBL, and the intrinsic clearance rate of NBL was increased by the pre-treatment with GL (39.49 ± 2.5 vs. 48.29 ± 3.4 µL/min/mg protein). The Caco-2 cell transwell experiments indicated that GL could increase the efflux ratio of NBL from 1.61 to 2.41.Discussion and conclusion: These results indicated that GL could change the pharmacokinetic profile of NBL, via increasing the metabolism and efflux of NBL in rats. It also suggested that the dose of NBL should be adjusted when co-administrated with GL in the clinic.

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis.

Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.

CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/ß-catenin signaling pathway.

The occurrence of chemo-resistance is an essential reason for the high morbidity of osteosarcoma (OS) patients. Circular RNAs (circRNAs) have been involved in the regulation of chemo-resistance in cancers. Semaphorins 6D (SEMA6D) is abnormally expressed in many cancers. However, the roles of circUBAP2 and SEMA6D in the chemo-resistance of OS are still unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circUBAP2, SEMA6D and microRNA-506-3p (miR-506-3p). The cisplatin resistance and proliferation of cells were evaluated by 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay. Western blot analysis was performed to measure the protein levels of Wnt/ß-catenin signaling pathway biomarkers and SEMA6D. Also, the apoptosis, migration and invasion of cells were assessed by Flow cytometry and Transwell assays, respectively. Besides, Dual-luciferase reporter assay was used to verify the interaction between miR-506-3p and circUBAP2 or SEMA6D. We found that the expression levels of circUBAP2 and SEMA6D were increased in cisplatin-resistant OS tissues and cells. Knockdown of circUBAP2 inhibited the cisplatin resistance, silenced Wnt/ß-catenin signaling pathway, hindered cell proliferation, migration and invasion, and promoted apoptosis in cisplatin-resistant OS cells, all of which could be reversed by overexpression of SEMA6D. MiR-506-3p could be sponged by circUBAP2 and could target SEMA6D. The suppression of miR-506-3p overexpression on the progression of OS cisplatin resistance could be reversed by SEMA6D overexpression, while miR-506-3p inhibitor also could invert the inhibitory effect of circUBAP2 silencing on the progression of OS cisplatin resistance. In conclusion, CircUBAP2 and SEMA6D played active roles in the progression of OS cisplatin resistance through miR-506-3p, which might provide some new ideas for studying the countermeasures of OS resistance.

Correction to: CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/ß-catenin signaling pathway.

The authors of the article want to add Xuelian Gong and Wei Li as the first author and co-first author as they have greatly contributed to the revision work. The correct author group is given in this Correction.

Axon-like protrusions promote small cell lung cancer migration and metastasis.

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

Ankyrin-B is a PI3P effector that promotes polarized α5ß1-integrin recycling via recruiting RabGAP1L to early endosomes.

Endosomal membrane trafficking requires coordination between phosphoinositide lipids, Rab GTPases, and microtubule-based motors to dynamically determine endosome identity and promote long-range organelle transport. Here we report that ankyrin-B (AnkB), through integrating all three systems, functions as a critical node in the protein circuitry underlying polarized recycling of α5ß1-integrin in mouse embryonic fibroblasts, which enables persistent fibroblast migration along fibronectin gradients. AnkB associates with phosphatidylinositol 3-phosphate (PI3P)-positive organelles in fibroblasts and binds dynactin to promote their long-range motility. We demonstrate that AnkB binds to Rab GTPase Activating Protein 1-Like (RabGAP1L) and recruits it to PI3P-positive organelles, where RabGAP1L inactivates Rab22A, and promotes polarized trafficking to the leading edge of migrating fibroblasts. We further determine that α5ß1-integrin depends on an AnkB/RabGAP1L complex for polarized recycling. Our results reveal AnkB as an unexpected key element in coordinating polarized transport of α5ß1-integrin and likely of other specialized endocytic cargos.