cytochrome-c-t and Precancerous-Conditions

Chronic inflammation promotes prostate cancer formation and progression. Furthermore, alterations in energy metabolism are a hallmark of prostate cancer cells. However, the actions of inflammatory factors on the energy metabolism of prostate epithelial cells have not been previously investigated. This is the first study to report on the effect of the inflammatory cytokine tumor necrosis factor alpha (TNFα) on the glycolytic and oxidative metabolism, and the mitochondrial function of widely used prostate epithelial cells.. Pre-malignant RWPE-1 and cancerous LNCaP and PC-3 cells were treated with low-dose TNFα. Glycolytic and oxidative metabolism was quantified by measuring extracellular acidification and oxygen consumption rates, respectively. ATP content and lactate export were measured by luminescence and fluorescence, respectively. Mitochondrial content and the expression of glucose transporter 1 (GLUT1), peroxisome proliferator-activated receptor co-activator 1 alpha (PGC-1α), and Cytochrome C were measured by flow cytometry.. Our data suggest that TNFα increases glycolysis, ATP production, and lactate export, while it reduces oxidative metabolism and mitochondrial function in prostate epithelial cells. The highly aggressive PC-3 cells tend to be less responsive to the actions of TNFα than the pre-malignant RWPE-1 and the non-aggressive LNCaP cells.. Cellular energetics, that is, glycolytic and oxidative metabolism is significantly influenced by low-level inflammation in prostate epithelial cells. In widely used prostate epithelial cell models, the micro-environmental inflammatory cytokine TNFα induces aerobic glycolysis while inhibiting oxidative metabolism. This supports the hypothesis that low-level inflammation can induce Warburg metabolism in prostate epithelial cells, which may promote cancer formation and progression.

Topics: Cell Line, Tumor; Cytochromes c; Disease Progression; Energy Metabolism; Epithelial Cells; Glucose Transporter Type 1; Glycolysis; Humans; Inflammation; Male; Mitochondria; Oxidative Stress; PPAR alpha; Precancerous Conditions; Prostate; Prostatic Neoplasms; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Hepatoma-derived growth factor (HDGF) is a novel multifunctional growth factor that elicits pleiotropic effects on biological processes such as lung remodeling and renal development. Recent studies demonstrated that HDGF is related to tumor proliferation, invasion, angiogenesis, and apoptosis. However, the molecular mechanism of HDGF's involvement in apoptosis remains to be clarified. In this study, we first analyze the role of HDGF in colorectal carcinoma (CRC) progression by immunohistochemistry. Then we used small interference RNA (HDGF-siRNA) to block HDGF and assessed its effect on inducing apoptosis of CRC loVo cells. Apoptosis was detected using flow cytometry (FCM), DNA ladder analysis, and Hoechst 33258 staining. In addition, the expression levels of some apoptosis-related proteins were examined by western blot. The result showed that HDGF expression gradually increased in the colorectal carcinogenesis process. Further studies demonstrated that knock-down of HDGF can down-regulate the survivin, activate the mitochondrial pathway, and induce apoptosis in loVo cells. These findings suggest that HDGF is involved in colorectal carcinogenesis process. Further blocking HDGF exhibits potent pro-apoptotic properties in colon cancer cells. Thus, HDGF might be a potential therapeutic target for human colorectal cancer. These findings may have major implications in the treatment of colorectal cancer.

Topics: Adenoma; Apoptosis; Blotting, Western; Cell Proliferation; Colitis; Colon; Colorectal Neoplasms; Cytochromes c; Female; Flow Cytometry; Humans; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Precancerous Conditions; Rectum; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering

We have already demonstrated that interferon alfa-2b (IFN-alpha2b) induces apoptosis in isolated hepatocytes from preneoplastic rat livers via the secretion of transforming growth factor beta(1) (TGF-beta(1)), and this process is accompanied by caspase-3 activation. The aim of this study was to further investigate the mechanism of this activation. Isolated hepatocytes from preneoplastic livers induced DNA fragmentation in response to IFN-alpha2b, which was completely blocked when anti-TGF-beta(1) was added to the culture media. IFN-alpha2b mediated radical oxygen species (ROS) production that preceded the loss of mitochondrial transmembrane potential (DeltaPsi), release of cytochrome c, and activation of caspase-3. Bax levels increased in a time-dependent fashion, and Bcl-x(L) was down-regulated in the early hours of IFN-alpha2b treatment. The delayed translocation of Bid into the mitochondria was in concordance with late caspase-8 activation. In conclusion, endogenous TGF-beta(1) secreted under IFN-alpha2b stimulus seems to induce cytochrome c release through a mechanism related to Bcl-2 family members and loss of mitochondrial DeltaPsi. Bax protein could be responsible of the release of cytochrome c during the initial hours of IFN-alpha2b-induced apoptosis via TGF-beta(1). Activated Bid by caspases could amplificate the mitochondrial events, enhancing the release of cytochrome c.

Topics: Animals; Annexin A5; Apoptosis; Caspase 3; Caspase 8; Cells, Cultured; Cytochromes c; DNA Fragmentation; Hepatocytes; Interferon alpha-2; Interferon-alpha; Liver; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reactive Oxygen Species; Recombinant Proteins; Transforming Growth Factor beta1