Franckhunter8171

Metastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are characterized as limiting steps for metastasis. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are opposite dynamic multistep processes that enable these critical events in metastasis by altering the phenotype of cancer cells and improving their ability to migrate, invade and seed at distant organs. Among the molecular pathways that promote tumorigenesis in late-stage cancers, transforming growth factor-β (TGF-β) is described as an EMT master inducer by controlling different genes and proteins related to cytoskeleton assembly, cell-cell attachment and extracellular matrix remodeling. Still, despite the successful outcomes of different TGF-β pharmacological inhibitors in cell culture (in vitro) and animal models (in vivo), results in cancer clinical trials are poor or inconsistent at least, highlighting the existence of crucial components in human cancers that have not been properly explored. Here we review most recent findings to provide perspectives bridging the gap between on-target anti-TGF-β therapies in vitro and in pre-clinical models and the poor clinical outcomes in treating cancer patients. Specifically, we focus on (i) the dual roles of TGF-β signaling in cancer metastasis; (ii) dynamic signaling; (iii) functional differences of TGF-β free in solution vs. in exosomes; (iv) the regulatory effects of tumor microenvironment (TME) - particularly by cancer-associated fibroblasts - on TGF-β signaling pathway. Clearly identifying and establishing those missing links may provide strategies to revitalize and clinically improve the efficacy of TGF-β targeted therapies.ASCT2 is a neutral amino acid transporter, which catalyzes a sodium-dependent obligatory antiport among glutamine and other neutral amino acids. The human ASCT2 over-expressed in Pichia pastoris and reconstituted in proteoliposomes has been employed for identifying alternative substrates of the transporter. The experimental data highlighted that hASCT2 also catalyzes a sodium-dependent antiport of glutamate with glutamine. This unconventional antiport shows a preferred sidedness glutamate is inwardly transported in exchange for glutamine transported in the counter direction. The orientation of the transport protein in proteoliposomes is the same as in the cell membrane; then, the observed sidedness corresponds to the transport of glutamate from the extracellular to the intracellular compartment. The competitive inhibition exerted by glutamate on the glutamine transport together with the docking analysis indicates that the glutamate binding site is the same as that of glutamine. The affinity for glutamate is lower than that for neutral amino acids, while the transport rate is comparable to that measured for the asparagine/glutamine antiport. this website Differently from the neutral amino acid antiport that is insensitive to pH, the glutamate/glutamine antiport is pH-dependent with optimal activity at acidic pH on the external (extracellular) side. The stimulation of glutamate transport by a pH gradient suggests the occurrence of a proton flux coupled to the glutamate transport. The proton transport has been detected by a spectrofluorometric method. The rate of proton transport correlates well with the rate of glutamate transport indicating a 11 stoichiometry H+ glutamate. The glutamate/glutamine antiport is also active in intact HeLa cells. On a physiological point of view, the described antiport could have relevance in some districts in which a glutamate/glutamine cycling is necessary, such as in placenta.Erythrocytes are among the most abundant cells in mammals and are perfectly adapted to their main functions, i.e., the transport of O2 to peripheral tissues and the contribution to CO2 transport to the lungs. In contrast to other cells, they are fully devoid of organelles. Similar to apoptosis of nucleated cells erythrocytes may enter suicidal death, eryptosis, which is characterized by the presentation of membrane phosphatidylserine on the cell surface and cell shrinkage, hallmarks that are also typical of apoptosis. Eryptosis may be triggered by an increase in the cytosolic Ca2+ concentration, which may be due to Ca2+ influx via non-selective cation channels of the TRPC family. Eryptosis is further induced by ceramide, which sensitizes erythrocytes to the eryptotic effect of Ca2+. Signaling regulating eryptosis further involves a variety of kinases including AMPK, PAK2, cGKI, JAK3, CK1α, CDK4, MSK1/2 and casein kinase. Eryptosis-dependent shrinkage is induced by K+ efflux through Ca2+-activated K+ channel KCa3.1, the Gardos channel. Eryptotic cells are phagocytosed and may adhere to endothelial cells. Eryptosis may help prevent hemolysis since defective erythrocytes usually undergo eryptosis followed by rapid clearance from circulating blood. Excessive eryptosis stimulated by various diseases and xenobiotics may result in anemia and/or impaired microcirculation. This review focuses on the significance and mechanisms of eryptosis as well as on the ion fluxes involved. Moreover, a short summary of further ion transport mechanisms of the erythrocyte membrane is provided.Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity.