Didscoidin domain receptor 1 (DDR1) is involved in the progression of prostate cancer metastasis through stimulation of epithelial-mesenchymal transition (EMT). So DDR1 inhibition can be a helpful target for cancer metastasis prevention. So, we studied the effects of DDR1 inhibition on EMT as well as induction of cell-cycle arrest and apoptosis in prostate cancer cell lines. DDR1 expression was evaluated using reverse-transcription polymerase chain reaction and western blot analysis. The EMT-associated protein expression was determined using the western blot analysis and immunocytochemistry following treatment with various concentrations of DDR1 inhibitor. The activation of DDR1 and also downstream-signaling molecules Pyk2 and MKK7 were determined using western blot analysis. Cell survival and proliferation after DDR1 inhibition were evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide, bromodeoxyuridine, and colony formation assays. Flow cytometry analysis was used to determine the effects of DDR1 inhibition on cellcycle arrest and apoptosis using annexin V/propidium iodide-based flow cytometry. Results showed that the protein expression of N-cadherin and vimentin were decreased whereas protein expression of E-cadherin was increased after DDR1 inhibition. Results of our western blot analysis indicated that DDR1 inhibitor effectively downregulated P-DDR1, P-Pyk2, and P-MKK7 levels. This result also showed that DDR1 inhibition decreased cell survival and proliferation, induced G1 cell-cycle arrest, induced apoptosis by an increase in the Bax/Bcl-2 ratio and depletion of the mitochondrial membrane potential, and also by reactive oxygen species creation in prostate cancer cells. These data show that DDR1 inhibition can result in the EMT prevention via inhibition of Pyk2 and MKK7 signaling pathway and induces cell-cycle arrest and apoptosis in prostate cancer cell lines. Thus, this study identifies DDR1 as an important target for modulating EMT and induction of apoptosis in prostate cancer cells. K E Y W O R D S apoptosis, cell-cycle arrest, discoidin domain receptor 1 (DDR1), EMT
Background:Bioflavonoids are well known for their multi directional biologic activity including antidiabetic effect. It has been demonstrated that flavonoids can act as insulin secretagogue or insulin mimetic agents.Objectives:This experimental study was designed in Arak University of Medical Sciences, Arak, Iran, to investigate the effects of biochanin A (a bioflavonoid) on fasting blood glucose (FBG), body weight, glycosylated hemoglobin (HbA1c), lipid profile, serum enzymes, and visfatin of streptozocin-induced diabetic rats.Patients and Methods:We used 24 male Wistar rats and randomly allocated them to four groups of six rats. One group was randomly assigned as control and diabetes was induced in three other groups by administration of streptozocin (35 mg/kg of body weight) intraperitoneally. The groups received the following treatments: group 1 (control), 5% DMSO; group 2 (diabetic control), 0.5% DMSO; and group 3 and 4, respectively 10 and 15 mg/kg biochanin A for 30 days. Body weight and biochemical parameters including FBG, HbA1c, lipid profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and visfatin were measured in all rats.Results:FBG level was significantly reduced in treated diabetic rats (139.8 ± 9.3 and 206 ± 11 mg/dL in groups 3 and 4, respectively) in comparison to the diabetic control (295.1 ± 14 mg/dL) (P < 0.05). Administration of biochanin A significantly decreased HbA1c in group 3 (6.66 ± 0.33) and group 4 (7.11 ± 0.31) in comparison to the diabetic control group (8.26 ± 0.44) (P < 0.05). Levels of serum visfatin were improved to near normal levels in the treated rats (249 ± 35.5 and 161.33 ± 13.07 in groups 3 and 4, respectively) in comparison to the diabetic control (302.17 ± 19.4) (P < 0.05). Furthermore, biochanin A showed a protective effect against weight loss in diabetic rats (P < 0.05). In treated rats, serum total cholesterol, triglyceride, and low-density lipoprotein cholesterol (LDL-c) were significantly decreased and high-density lipoprotein (HDL-c) was increased in comparison with the diabetic control group. In addition, biochanin A restored the altered plasma enzymes (AST, ALT, and ALP) activities to near normal. Histopathologic examination of the pancreas also indicated that biochanin A had protective effects on β-cells in streptozocin-induced diabetic rats.Conclusions:This study demonstrated that biochanin A possessed hypoglycemic and antilipemic activities and could increase visfatin expression, which suggests its beneficial effect in the treatment of diabetes.
Integrin α2β1 plays an important role in cellular migration and metastasis processes associated with prostate cancer. The aim of this study was to assess whether selective inhibition of integrin α2β1 is an effective strategy to target metastatic prostate cancer cells. In this regard, we examined the effects of the inhibitor BTT‐3033, which selectively interferes with the connection between integrin a2b1 and its ligand, on migration, epithelial–mesenchymal transition (EMT), cell cycle arrest, apoptosis, and specific intracellular signaling pathways using LNcap‐FGC and DU‐145 prostate cancer cell lines. Western blot analysis and immunocytochemistry assays showed that inhibition of integrin a2b1 inhibits EMT, through the increased expression of E‐cadherin and decreased expression of N‐cadherin and vimentin. Scratch wound healing assays revealed a direct effect on integrin α2β1 in the migration capacity of cells. In addition, treatment with BTT‐3033 induced a reduction in cell viability and proliferation, as assessed by MTT and BrdU assays. In addition, the results show that BTT‐3033 inhibits cell proliferation by inducing G1 cell cycle arrest. Moreover, inhibition of integrin α2β1 induces apoptosis through the activation of ROS, Bax protein upregulation, caspase‐3 activation, and depletion of ΔΨm. Molecular signaling studies showed that integrin α2β1 was a positive regulator of MKK7 phosphorylation. In conclusion, our results reveal a critical role for integrin a2b1 in the proliferation of prostate cancer cells, as demonstrated by EMT inhibition, cell cycle arrest, and apoptosis induction in response to treatment with its specific inhibitor BT‐3033.
Reboxetine, as an adjuvant to haloperidol, may have a helpful effect on the deficit syndrome of schizophrenia.
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