The importance of Src signaling in sarcoma

Abstract

Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

Sphingosine‐1‐phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR‐101 expression

“…Src, a proto‐oncogene encoding the nonreceptor tyrosine kinase, regulates several intracellular signaling pathways implicated in multistep processes of tumorigenesis, including the promotion of epithelial–mesenchymal transition, angiogenesis, migration, and invasion, as well as the inhibition of apoptosis (Chen et al ., 2015b). At least three downstream signaling pathways are involved in the Src‐regulated cellular effects, including the mitogen‐activated protein kinase (MAPK), the phosphatidylinositol 3‐kinase (PI3K), and the signal transducer and activator of transcription 3 (STAT3) pathways (Wu et al ., ; Zhang et al ., ).…”

The Different Conformational States of Tissue Transglutaminase Have Opposing Affects on Cell Viability

“…Thus, a picture is starting to emerge where tTG plays important roles as a protein scaffold functioning in EGFR signaling as well as possibly in the actions of other growth factor receptors that signal through c-Src and PI 3-kinase (51,52). When in its GTP-bound state, tTG would be capable of assembling signaling partners and regulators in a manner that sustains EGFRsignaling lifetimes and enhances PI 3-kinase activation (10, 28).…”

Differentially activated Src kinase in chemo‐naïve human primary osteosarcoma cells and effects of a Src kinase inhibitor

“…Src deregulation in cancer primarily involves protein overexpression and abnormalities in Src kinase activity, mostly due to auto‐phosphorylation of tyrosine 416 ( ), which can in turn activate specific signaling pathways by phosphorylating the target proteins, thus constituting an amplification cascade of a network regulation system . Although different sarcoma cells and tissue specimens showed to possess hyper‐phosphorylated Src 416 , to date Src activation levels (both Src 416 hyper‐phosphorylation and total Src amount) remained still fully unexplored in human primary OS chemo‐naïve cells which are known to be invaluable biological systems for the study of the molecular basis of the disease and the development of novel targeted therapeutic approaches . To our knowledge, this is the first study on the basal activation state of Src kinase in patient derived chemo‐naïve cells (compared to human primary osteoblasts, HOb) and the possible correlation between levels of pSrc 416 and Src‐tot and OS subtype.…”