Lipid rafts control human melanoma cell migration by regulating focal adhesion disassembly

Tumor cell migration is a crucial step in the metastatic cascade, and interruption of this step is considered to be logically effective in preventing tumor metastasis. Lipid rafts, distinct liquid ordered plasma membrane microdomains, have been shown to influence cancer cell migration, but the underlying mechanisms are still not well understood. Here, we report that lipid rafts regulate the dynamics of actin cytoskeleton and focal adhesion in human melanoma cell migration. Disrupting the integrity of lipid rafts with methyl-β cyclodextrin enhances actin stress fiber formation and inhibits focal adhesion disassembly, accompanied with alterations in cell morphology. Furthermore, actin cytoskeleton, rather than microtubules, mediates the lipid raft-dependent focal adhesion disassembly by regulating the dephosphorylation of focal adhesion proteins and the internalization of β3 integrin. We also show that Src–RhoA–Rho kinase signaling pathway is responsible for lipid raft disruption-induced stress fiber formation. Taken together, these observations provide a new mechanism to further explain how lipid rafts regulate the migration of melanoma cell and suggest that lipid rafts may be novel and attractive targets for cancer therapy.     

c-Abl Kinase Is a Regulator of αvβ3 Integrin Mediated Melanoma A375 Cell Migration

Integrins are heterodimeric transmembrane receptors that physically link the extracellular matrix (ECM) to the intracellular actin cytoskeleton, and are also signaling molecules that transduce signals bi-directionally across the plasma membrane. Integrin regulation is essential for tumor cell migration in response to growth factors. c-Abl kinase is a nonreceptor tyrosine kinase and is critical for signaling transduction from various receptors. Here we show that c-Abl kinase is involved in A375 cell migration mediated by α_vβ₃ integrin in response to PDGF stimulation. c-Abl kinase colocalizes with α_vβ₃ integrin dynamically and affects α_vβ₃ integrin affinity by regulating its cluster. The interaction between c-Abl kinase and α_vβ₃ integrin was dependent on the activity of c-Abl kinase induced by PDGF stimulation, but was not dependent on the binding of α_vβ₃ integrin with its ligands, suggesting that c-Abl kinase is not involved in the outside-in signaling of α_vβ₃ integrin. Talin head domain was required for the interaction between c-Abl kinase and α_vβ₃ integrin, and the SH3 domain of c-Abl kinase was involved in its interaction with talin and α_vβ₃ integrin. Taken together, we have uncovered a novel and critical role of c-Abl kinase in α_vβ₃ integrin mediated melanoma cell migration.     

Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness

Monocyte infiltration into inflammatory sites is generally preceded by neutrophils. We show here that neutrophils may support this process by activation of CCL15, a human chemokine circulating in blood plasma. Neutrophils were found to release CCL15 proteolytic activity in the course of hemofiltration of blood from renal insufficiency patients. Processing of CCL15 immunoreactivity (IR) in the pericellular space is suggested by a lack of proteolytic activity in blood and blood filtrate, but a shift of the retention time (t(R)) of CCL15-IR, detected by chromatographic separation of CCL15-IR in blood and hemofiltrate. CCL15 molecules with N-terminal deletions of 23 (delta23) and 26 (delta26) aa were identified as main proteolytic products in hemofiltrate. Neutrophil cathepsin G was identified as the principal protease to produce delta23 and delta26 CCL15. Also, elastase displays CCL15 proteolytic activity and produces a delta21 isoform. Compared with full-length CCL15, delta23 and delta26 isoforms displayed a significantly increased potency to induce calcium fluxes and chemotactic activity on monocytes and to induce adhesiveness of mononuclear cells to fibronectin. Thus, our findings indicate that activation of monocytes by neutrophils is at least in part induced by quantum proteolytic processing of circulating or endothelium-bound CCL15 by neutrophil cathepsin G.     

Haptoglobin gene promoter polymorphism and haplotypes are unique in different populations

We investigated the distribution of haptoglobin (HP) alleles and haplotypes among Africans (Ghanaians), Europeans (from South Africa), and Chinese. HP*1F was present only in Africans and Europeans, whereas HP*del was unique to Chinese. Six base substitutions at the promoter region were population specific. Only 3 out of 18 haplotypes were shared among the populations. A probable application of HP in human population genetics appears legitimate.     

Therapeutic potential of HIV-1 entry inhibitor peptidomimetics

Human immunodeficiency virus 1 (HIV-1) infection remains a public health concern globally. Although great strides in the management of HIV-1 have been achieved, current highly active antiretroviral therapy is limited by multidrug resistance, prolonged use-related effects, and inability to purge the HIV-1 latent pool. Even though novel therapeutic options with HIV-1 broadly neutralizing antibodies (bNAbs) are being explored, the scalability of bNAbs is limited by economic cost of production and obligatory requirement for parenteral administration. However, these limitations can be addressed by antibody mimetics/peptidomimetics of HIV-1 bNAbs. In this review we discuss the limitations of HIV-1 bNAbs as HIV-1 entry inhibitors and explore the potential therapeutic use of antibody mimetics/peptidomimetics of HIV-1 entry inhibitors as an alternative for HIV-1 bNAbs. We highlight the reduced cost of production, high specificity, and oral bioavailability of peptidomimetics compared to bNAbs to demonstrate their suitability as candidates for novel HIV-1 therapy and conclude with some perspectives on future research toward HIV-1 novel drug discovery.     

Associations of IL13 gene polymorphisms and immune factors with Schistosoma haematobium infection in schoolchildren in four schistosomiasis-endemic communities in Ghana

BackgroundSchistosomiasis remains a major public health issue with over 90% of the prevalence rates recorded in Sub-Saharan Africa. In this study, the relationships between different interleukin gene polymorphisms (IL-13-591A/G, IL-13-1055C/T, IL-13-1258A/G) and Schistosoma haematobium infection levels were evaluated; as well as the host plasma antibodies and cytokine profiles associated with schistosomiasis infection.MethodologyA total of 469 school children aged 6 to 19 years from four schistosomiasis-endemic communities in Ghana were involved. Single urine and stool samples were obtained from each pupil, processed via sedimentation and Kato-Katz, and examined via microscopy for Schistosoma and soil-transmitted helminth (STH) eggs. Next, venous blood samples were drawn from 350 healthy pupils, and used to measure antibody and plasma cytokine levels by ELISA. Single nucleotide polymorphisms in the IL-13 gene were genotyped on 71 selected blood samples using the Mass Array technique.Principal findings and conclusionThe overall prevalence of urinary schistosomiasis was 21.11%. Community-level prevalences were 17.12%, 32.11%, 20.80%, and 15.32% for Asempaneye, Barikumah, Eyan Akotoguah, and Apewosika respectively. Generally, higher S. haematobium infection prevalence and intensity were recorded for participants with genotypes bearing the IL13-1055C allele, the IL13-591A, and the IL13-1258A alleles. Also, higher S. haematobium infection prevalence was observed among participants in the 12-14-year age group with the IL13-1055C, IL13-591A, and IL13-1258A alleles. Interestingly, higher STH prevalence was also observed among participants with the IL13-1055C, IL13-591A, and IL13-1258A alleles. Furthermore, the age-associated trends of measured antibodies and cytokines of S. haematobium-infected school-children depicted a more pro-inflammatory immune profile for pupils aged up to 1l years, and an increasingly anti-inflammatory profile for pupils aged 12 years and above. This work provides insight into the influence of IL-13 gene polymorphisms on S. haematobium, and STH infections, in school-aged children (SAC).