Midkine: an emerging target of drug development for treatment of multiple diseases

Abstract

Midkine is a multifunctional factor and has anti‐apoptotic, migration‐promoting, angiogenic, anti‐microbial and other activities. Midkine ameliorates ischemic injury in the heart and brain, enhances oocyte maturation, and is involved in neurogenesis. On the other hand, midkine is an important factor in the etiology of various diseases, especially those with inflammatory backgrounds. Furthermore, midkine is overexpressed in most malignant tumors and plays roles in their invasive phenotypes as well as in their resistance to chemotherapeutics. Therefore, midkine itself is expected to be useful for the treatment of brain and heart diseases, while midkine inhibitors are promising for the treatment of malignant tumors, multiple sclerosis, restenosis, renal diseases, hypertension and osteoporosis. Blood levels of midkine are also expected to be helpful as disease markers, especially as cancer markers. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit

Serum midkine as a surrogate biomarker for metastatic prediction in differentiated thyroid cancer patients with positive thyroglobulin antibody

“…MK is such an important multi-functional heparin-binding growth factor, which regulates cell growth, survival, migration, angiogenic, and anti-apoptotic activities2425. MK is rich in both basic amino acids and cysteine26, and is the founding member of a small protein family, the other member of which is pleiotrophin2728.…”

“…MK is strongly expressed during embryonic periods, and is crucial in embryonic development, yet its expression in adult tissues is generally very weak. However, MK plays important roles in various pathogenesis, in particular malignant diseases1925. MK is generally composed of two domains, namely a more N-terminally located N-domain and a more C-terminally located C-domain2429.…”

“…MK signaling is largely mediated by cell surface receptors like PTPζ30. Furthermore, multiple kinases like MAPK and PI3K are important in the downstream signaling system242531. MK over-expression has been reported in diverse oncology settings (for at least 20 different cancer types as pointed out by Jones19), making MK a “pan-cancer” biomarker.…”

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

“…MK is highly correlated with cancer resistance and EMT (9,10,14). Wnt ligands bind to Frizzled-LRP5/6 receptor complexes and activate the cytoplasmic scaffold protein, Dishevelled, resulting in inhibition of β-catenin phosphorylation and degradation (38).…”

“…MK exhibits its activity through several receptors, including anaplastic lymphoma kinase, proteine tyrosine phosphatase ζ, Notch 2, low density lipoprotein receptor-related protein (LRP), proteoglycans and integrins. MK has significant roles in inflammation immunity, blood pressure, development, tissue protection/renewal/repair, cancer [including tumor growth, chemoresistance, transformation, anti-apoptosis, epithelial-mesenchymal transition (EMT)] and determination of cell fate (from autophagy to cell resistance/survival or autophagic cell death/apoptosis) (8)(9)(10)(11)(12). High MK expression has been observed in several cancer types, including PCa, in preclinical and clinical studies (9,13,14).…”