The helicase, DDX3X, interacts with poly(A)-binding protein 1 (PABP1) and caprin-1 at the leading edge of migrating fibroblasts and is required for efficient cell spreading.

DDX3X, a helicase, can interact directly with mRNA and translation initiation factors, regulating the selective translation of mRNAs that contain a structured 5' untranslated region. This activity modulates the expression of mRNAs controlling cell cycle progression and mRNAs regulating actin dynamics, contributing to cell adhesion and motility. Previously, we have shown that ribosomes and translation initiation factors localise to the leading edge of migrating fibroblasts in loci enriched with actively translating ribosomes, thereby promoting steady-state levels of ArpC2 and Rac1 proteins at the leading edge of cells during spreading. As DDX3X can regulate Rac1 levels, cell motility and metastasis, we have examined DDX3X protein interactions and localisation using many complementary approaches. We now show that DDX3X can physically interact and co-localise with poly(A)-binding protein 1 and caprin-1 at the leading edge of spreading cells. Furthermore, as depletion of DDX3X leads to decreased cell motility, this provides a functional link between DDX3X, caprin-1 and initiation factors at the leading edge of migrating cells to promote cell migration and spreading.

Probing the Anticancer Action of Novel Ferrocene Analogues of MNK Inhibitors.

Two novel ferrocene-containing compounds based upon a known MNK1/2 kinase (MAPK-interacting kinase) inhibitor have been synthesized. The compounds were designed to use the unique shape of ferrocene to exploit a large hydrophobic pocket in MNK1/2 that is only partially occupied by the original compound. Screening of the ferrocene analogues showed that both exhibited potent anticancer effects in several breast cancer and AML (acute myeloid leukemia) cell lines, despite a loss of MNK potency. The most potent ferrocene-based compound 5 was further analysed in vitro in MDA-MB-231 (triple negative breast cancer cells). Dose⁻response curves of compound 5 for 2D assay and 3D assay generated IC50 values (half maximal inhibitory concentration) of 0.55 µM and 1.25 µM, respectively.

Transition of patients with Gaucher disease type 1 from pediatric to adult care: results from two international surveys of patients and health care professionals.

Introduction: Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. The most common subtype in Europe and the USA, type 1 (GD1), is characterized by fatigue, cytopenia, splenomegaly, hepatomegaly, bone disease, and rarely pulmonary disease. Increased life expectancy brought about by improved treatments has led to new challenges for adolescents and their transition to adult care. Efficient healthcare transition to adult care is essential to manage the long-term age-related complications of the disease. Methods: This international study consisted of two online surveys: one survey for patients with GD1 and one survey for healthcare professionals (HCPs) involved in treatment of patients with GD1. The aims of this international, multi-center project were to evaluate the current transition process in various countries and to understand the challenges that both HCPs and patients experience. Results: A total of 45 patients and 26 HCPs took part in the survey, representing 26 countries. Our data showed that a third (11/33) of patients were aware of transition clinics and most stated that the clinic involved patients with metabolic diseases or with GD. Seven patients attended a transition clinic, where most patients (5/7) received an explanation of the transition process. Approximately half of HCPs (46%; 12/26) had a transition clinic coordinator in their healthcare center, and 10 of HCPs had a transition clinic for patients with metabolic diseases in their healthcare center. HCPs reported that transition clinics were comprised of multi-disciplinary teams, with most patients over the age of 18 years old managed by hematology specialists. The main challenges of the transition process reported by HCPs included limited funding, lack of expertise and difficulty coordinating care amongst different specialties. Discussion: Our study demonstrates the lack of a standardized process, the need to raise awareness of transition clinics amongst patients and the differences between the transition process in different countries. Both patients and HCPs expressed the need for a specialist individual responsible for transition, efficient coordination between pediatricians and adult specialists and for patient visits to the adult center prior to final transition of care.

Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells.

The study of eukaryotic initiation factor 4E (eIF4E) is a key focus in cancer research due to its role in controlling the translation of tumour-associated proteins, that drive an aggressive migratory phenotype. eIF4E is a limiting component of the eIF4F complex which is a critical determinant for the translation of mRNAs. Mitogen-activated protein kinase interacting protein kinases (MNK1/2) phosphorylate eIF4E on Ser209, promoting the expression of oncogenic proteins, whereas mTORC1 phosphorylates and de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Here we show that inhibiting these pathways simultaneously effectively slows the rate of cell migration in breast cancer cells. However, a molecular hybridisation approach using novel, cleavable dual MNK1/2 and PI3K/mTOR inhibiting hybrid agents was less effective at slowing cell migration.

Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers.

Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.