ABSTRACT
Glycogen synthase kinaseî3 (GSKî3α and GSKî3ß) are serine/threonine protein kinases acting on numerous substrates and involved in the regulation of various cellular functions such as their proliferation, survival, glycogen metabolism, and autophagy. Accumulating evidence indicates that the expression of GSKî3α is increased mainly in androgenîdependent while that of GSKî3ß in androgenîindependent prostate cancer, and that GSKî3ß is also involved in the regulation of the transactivation of the androgen receptor (AR) and growth of prostate cancer. Animal experiments have proved that some GSKî3 inhibitors, such as lithium, can significantly suppress tumor growth in different animal models of prostate cancer. The GSKî3 inhibitor is promising to be an important agent for the clinical management of prostate cancer.
Subject(s)
Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3/metabolism , Neoplasm Proteins/metabolism , Prostatic Neoplasms/enzymology , Androgens , Animals , Cell Line, Tumor , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Humans , Male , Neoplasms, Hormone-Dependent/enzymology , Neoplasms, Hormone-Dependent/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Receptors, Androgen/metabolismABSTRACT
AIM: To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells (HSCs) and whether Hes1 is regulated by transforming growth factor (TGF)/bone morphogenetic protein (BMP) signaling. METHODS: Immunofluorescence staining was used to detect the expression of desmin, glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin (α-SMA) after freshly isolated, normal rat HSCs had been activated in culture for different numbers of days (0, 1, 3, 7 and 10 d). The expression of α-SMA, collagen1α2 (COL1α2), Notch receptors (Notch1-4), and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction. Luciferase reporter assays and Western blot were used to study the regulation of α-SMA, COL1α1, COL1α2 and Hes1 by NICD1, Hes1, CA-ALK3, and CA-ALK5 in HSC-T6 cells. Moreover, the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated. RESULTS: The expression of Notch1 and Hes1 mRNAs was significantly down-regulated during the culture of freshly isolated HSCs. In HSC-T6 cells, Notch1 inhibited the promoter activities of α-SMA, COL1α1 and COL1α2. On the other hand, Hes1 enhanced the promoter activities of α-SMA and COL1α2, and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy. Furthermore, co-transfection of pcDNA3-CA-ALK3 (BMP signaling activin receptor-like kinase 3) and pcDNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells, while pcDNA3-CA-ALK5 (TGF-ß signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression. CONCLUSION: Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2, and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.