Melusin Promotes a Protective Signal Transduction Cascade in Stressed Hearts.

Melusin is a chaperone protein selectively expressed in heart and skeletal muscles. Melusin expression levels correlate with cardiac function in pre-clinical models and in human patients with aortic stenosis. Indeed, previous studies in several animal models indicated that Melusin plays a broad cardioprotective role in different pathological conditions. Chaperone proteins, besides playing a role in protein folding, are also able to facilitate supramolecular complex formation and conformational changes due to activation/deactivation of signaling molecules. This role sets chaperone proteins as crucial regulators of intracellular signal transduction pathways. In particular Melusin activates AKT and ERK1/2 signaling, protects cardiomyocytes from apoptosis and induces a compensatory hypertrophic response in several pathological conditions. Therefore, selective delivery of Melusin gene in the heart via cardiotropic adenoviral associated virus serotype 9 (AAV9), may represent a new promising gene-therapy approach for different cardiac pathologies

Escaping NK cells and recruiting neutrophils: How Morgana/NF-κB signaling promotes metastasis

Cancer cells escape immune surveillance and induce immune cell aberrant activation to support tumour growth and progression. We recently reported that Morgana/NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling in breast cancer cells is responsible for NK (Natural Killer) cell inactivation and neutrophil recruitment in the primary tumour and in the lung pre-metastatic niche

The double face of Morgana in tumorigenesis

Morgana is a chaperone protein able to bind to ROCK I and II and to inhibit their kinase activity. Rho kinases are multifunctional proteins involved in different cellular processes, including cytoskeleton organization, centrosome duplication, cell survival and proliferation. In human cancer samples Morgana appears to be either downregulated or overexpressed, and experimental evidence indicate that Morgana behaves both as an oncosuppressor and as a proto-oncogene. Our most recent findings demonstrated that if on the one hand low Morgana expression levels, by inducing ROCK II hyperactivation, cause centrosome overduplication and genomic instability, on the other hand, Morgana overexpression induces tumor cell survival and chemoresistance through the ROCK I-PTEN-AKT axis. Therefore, Morgana belongs to a new class of proteins, displaying both oncogenic and oncosuppressor features, depending on the specific cellular context

Redox aspects of chaperones in cardiac function

Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury

Targeting few to help hundreds: JAK, MAPK and ROCK pathways as druggable targets in atypical chronic myeloid leukemia

Abstract Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients

P03.25 Neutralizing extracellular CHP-1 impairs tumor growth and metastasis formation

Background Found in the extracellular compartment, Heat Shock Proteins (HSPs) are actively secreted proteins that modulate the tumor behavior. Extracellular HSPs play a unique role as extracellular chaperones and receptors-binding molecules, favoring the establishment and maintenance of different cancer hallmarks, including immune modulation and evasion. CHP-1, is a ubiquitously expressed protein with chaperone activity and its high expression correlates with high tumor grade and lymph node positivity in different breast and lung cancer subtypes. In addition, CHP-1 is actively and uncanonically secreted by cancer cells in the tumor microenvironment (TME). Materials and Methods Sera cancer patients were analyzed for the presence of CHP-1. To assess the role of extracellular CHP-1 (eCHP-1) in the TME, in vitro experiments on different cell populations have been performed. To dissect the molecular mechanisms, through which eCHP-1 induces cancer progression, have been analyzed specific signaling pathways in cancer and immune cells. Immune cell composition in presence of eCHP-1 in tumors has been identified using flow-cytometry. The characterization of eCHP-1 inhibition as therapeutic approach has been conducted in breast and colon cancer pre-clinical models. Results eCHP-1 activates an autocrine signaling through TLR2, TLR4 and LRP1, promoting tumor progression and metastasis formation in different pre-clinical models. Moreover, eCHP-1 can modulate the immune composition of the TME, making interesting the analysis of its inhibition in cancer immunotherapy. Conclusions eCHP-1 represents a easy accessible protein for diagnosis and targeting in very aggressive canncers. Disclosure Information L. Secli: None. F. Fusella: None. M. Brancaccio: None