ABSTRACT
Midkine (MK) is a heparin-binding anti-apoptotic growth factor or cytokine also known as neurite growth-promoting factor 2 (NEGF2). It is developmentally an important retinoic acid-responsive gene product strongly induced during the mid-gestation stage. Midkine promotes different cellular events such as cell growth, differentiation, survival, gene expression, and drug resistence. Midkine, the phosphatidylinositol 3-kinases (PI3-kinase, PI3K) and glycogen synthase kinase-3 beta (GSK-3ß) inhibitors together with lithium chloride may be a very effective treatment modality, especially in tumors with high expression of these two molecules. PI3 kinase and GSK-3ß, both serine threonine kinases located in the center of the signaling network, are very important regulator molecules for cell survival or death. Lithium chloride (LiCl), with its newly discovered antineoplastic effect and cytotoxicity potentiation, has become a promising agent in the application of new combination treatments. Although the LiCl mechanism of action is still not fully understood, previous studies have shown that LiCl is an inhibitör of the inositol monophosphatase (IMPase) and GSK-3ß. GSK-3ß, is a serine-threonine protein kinase involved in cell proliferation, differentiation, survival, apotosis, and tumorogenesis. The role of GSK-3ß in tumorigenesis and cancer remains controversial. It may have a function as a tumor suppressor for certain types of tumors, but it promotes cell growth and development in other tumor types.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Lithium Chloride/pharmacology , Lithium Chloride/therapeutic use , Midkine/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Biomarkers , Gene Expression Regulation , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Membrane Glycoproteins/metabolism , Midkine/antagonists & inhibitors , Midkine/chemistry , Midkine/genetics , Neoplasms/etiology , Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Receptors, Growth Factor/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Midkine (MK) is a heparin-binding growth factor that markedly expressed during embryogenesis but downregulated to inconsiderable levels in healthy adults. However, MK is upregulated during tissue repair and in many pathologic conditions, mostly malignancies and inflammatory diseases. MK promotes a number of functions in target cells such as migration, proliferation, survival, growth, reproduction and repair, angiogenesis, and gene expression. It acts as a pro-inflammatory cytokine and contributes to chronic inflammation via promoting chemotaxis and tissue infiltration of neutrophils and macrophages. Furthermore, MK upregulated the production of various inflammatory mediators (i.e. interleukin (IL) 6 and IL8). Recent studies have demonstrated strong evidence that MK is involved in the onset and progression of autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) and other autoimmune conditions such as multiple sclerosis (MS). Additionally, it has been shown that MK is overexpressed in two major clinically defined forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), which are classified as autoinflammatory diseases. Taken together, MK is involved in the pathogenesis of autoimmune and autoinflammatory diseases and may serve as an indicator and biomarker in these conditions. Furthermore, MK inhibitors are expected to contribute in the management of these diseases.
