ABSTRACT
ACK1 (activated Cdc42-associated kinase) is a non-receptor tyrosine kinase, originally identified by its binding to the GTP-binding small GTPase Cdc42. It is widely expressed in human tissues and activated by various extracellular growth factors such as EGF, PDGF and TGF-β. The activated ACK1 mediates the signaling cascade by interacting with downstream effectors followed by their phosphorylation. In recent years, researchers have investigated the biological functions of ACK1 and its roles in cancer research. The gene amplification and overexpression of ACK1 is associated with a poor prognosis and metastasis in a variety of cancers including lung, ovarian and prostate cancers. Therefore, the development of small molecule inhibitors of ACK1 provides promising opportunities for cancer-targeted therapy. In this review, we briefly describe recent advances in understanding the activation and biological function of ACK1 and introduce its novel inhibitors with potential therapeutic activities in preclinical studies.
ABSTRACT
Objective: To compare the influences of retrorsine on hepatocytes proliferation in mice and rats after liver injury, so as to investigate the feasibility of using retrorsine for establishment of liver cell transplantation model in mice. Methods: Male mice and rats were pretreated with 2 injections of retrorsine (70 mg/kg for mice and 30 mg/kg for rats) (as retrorsine-treated group, n=30) at 2 weeks interval or saline (as non-treated group, n=30). A single injection of carbon tetrachloride (CCl4, 0. 5 mg/kg) was given to all animals 4 weeks after the final injection of retrorsine or saline. At 0(before administration), 1, 2, 3, 4, 6, 15 d after CCl4 administration, the animals were sacrificed and their livers were subjected to H-E staining and Ki-67 antibody immunohistochemistry analysis to evaluate the pathological changes and hepatocyte proliferation. Results: The liver in rats treated with retrorsine displayed obvious megalocytosis, small bile duct hyperplasia, and small hepatocyte hyperplasia (forming nodule); no such changes were found in non-treated group. However, the liver in mice treated with retrorsine displayed hepatocyte degeneration and necrosis in the perivenous areas and the same was true to the liver in non-treated mice. Ki-67 immunohistochemistry analysis showed that in rats treated with retrorsine, the positive hepatocytes, mainly found in small hepatocyte nodules, were obviously less than those in control group 3 d after CCl4 administration(P<0.05). Ki-67 positive hepatocytes in mice treated with retrorsine were abundant and almost more than those in control group at all time points, especially 4 d after CCl4 administration(P<0.01), with the same changing tendency in both groups. Conclusion: Retrorsine can obviously inhibit hepatocyte proliferation after liver injury and is suitable for liver cell transplantation in rats, while it is the contrary in mice.
ABSTRACT
To investigate the differences of proliferation capacity and phenotype properties of mesenchymal stem cells (MSCs) derived from bone marrow (BM) of aplastic anemia patients, fetuses and children, MSCs were isolated from BM of patients with aplastic anemia and expanded in vitro; MSCs derived from BM of fetuses and children were used as normal control groups, three sources of MSCs were compared by morphology, in vitro proliferation capacity, phenotype and immunocytochemistry. The results showed that MSCs could be isolated and expanded from aplastic anemia patient BM. MSCs derived from BM of aplastic anemia patients shared a similar morphology and phenotype with derived MSCs from BM of fetuses and children. However, in vitro proliferation capacity of MSCs derived from BM of aplastic anemia patients after 20 population doublings (PD) was significantly lower, compared with MSCs from BM of fetuses and children. BM MSCs derived from children and fetuses proliferated for more than 30 PD. It is concluded that BM MSCs from aplastic anemia patients appears to be normal in phenotype but their proliferation capacity is lower in comparison with control groups.