dorsomorphin and Prostatic-Neoplasms

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of death in Western countries. Clinically, screening drugs and develop developing new therapeutics to treat PCa is of great significance. In this study, BML-275 was demonstrated to exert potent antitumor effects in PCa by antagonizing mTOR activity. In cultured PCa cells, BML-275 treatment reduced the expression levels of c-Myc and survivin, promoted the activation of p53, and thereby induced p21/cyclin D1/CDK4/6-dependent cell cycle G1/S arrest. As a result, BML-275 inhibited cellular proliferation and induced mitochondrial-mediated apoptosis. In addition, BML-275 treatment triggered autophagy. Interestingly, EACC-mediated suppression of autophagy did not affect BML-275-induced proliferation and apoptosis. Nude mouse tumorigenic experiments also confirmed that BML-275 inhibited PCa growth, induced PCa cell apoptosis and autophagy. Mechanistically, the activities of PI3K/AKT and AMPK pathways were downregulated by BML-275 treatment in vitro and in vivo. Importantly, mTOR, a common downstream negative protein of PI3K/AKT and AMPK signaling, was induced to inactivate, which may be associated with the induction of apoptosis and autophagy. The pharmacological activation of mTOR by MHY1485 abolished the induction of apoptosis and autophagy of BML-275. Molecular docking results showed that BML-275 can bind to the FKRP12-rapamycin binding site on mTOR protein, and thereby may have the same inhibitory activity on mTOR as rapamycin. Thus, these findings indicated that BML-275 induces mitochondrial-mediated apoptosis and autophagy in PCa by targeting mTOR inhibition. BML-275 may be a potential candidate for the treatment of PCa.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagy; Humans; Male; Mice; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

Alternol is an original compound purified from the fermentation products of Alternaria alternata var. monosporus, a microorganism from the bark of the yew tree. It has been reported that Alternol can inhibit proliferation of mouse leukemia cells and human gastric carcinoma cells, the aim of this study was to investigate the effects of Alternol on prostate cancer cells in comparison to prostate cells.. The MTT assay was utilized to assess cell viability. Cell cycle was analyzed by flow cytometry with propidium iodide staining. Protein expression levels were examined by Western blotting.. Alternol treatment resulted in a significant decrease in the viability of prostate cancer cells but had lesser effects on prostate cells. Alternol inhibited AMP-activated protein kinase (AMPK) phosphorylation in prostate cancer C4-2 cells but stimulated AMPK phosphorylation in prostate RWPE-1 cells. Inhibition of p27 phosphorylation was observed in C4-2 cells whereas a promotion of p27 phosphorylation was seen in RWPE-1 cells. Alternol treatment resulted in a profound increase in the LC3II/LC3I protein ratio in RWPE-1 cells but not in C4-2 cells. A dose-dependent down-regulation of Bcl-2 protein was detected in C4-2 cells but not in RWPE-1 cells. Pretreatment of cells with Compound C (AMPK inhibitor) before Alternol treatment abolished the selective antitumor effect of Alternol.. These results reveal for the first time that Alternol exerts a selective antitumor effect on prostate cancer cells when compared with RWPE-1 prostate epithelial cells. In addition, the AMPK signaling pathway is responsible for the selective antitumor effects of Alternol.

Topics: AMP-Activated Protein Kinases; Autophagy; Blotting, Western; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Drug Interactions; Flow Cytometry; Formazans; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Phosphorylation; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Signal Transduction; Tetrazolium Salts

Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells.. Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis.. IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK alpha subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21(waf/cip) as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further.. We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21(waf/cip) and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21(waf/cip) pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

Topics: AMP-Activated Protein Kinases; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; DNA-Binding Proteins; Enzyme Activation; Female; G2 Phase; Humans; Lung Neoplasms; Male; Metformin; Morpholines; Phosphorylation; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Pyrones; Radiation Tolerance; RNA, Small Interfering; Tumor Suppressor Protein p53; Tumor Suppressor Proteins