4-hydroxy-2-nonenal and Bone-Neoplasms

The onset of lipid peroxidation within cellular membranes is associated with changes in their physiochemical properties and enzymatic dysfunction of the membrane environment. There are increasing bodies of evidence indicating that aldehydic molecules generated endogenously during the process of lipid peroxidation are causally involved in most of the pathophysiological effects associated with oxidative stress in cells and tissues. 4-Hydroxy-2-nonenal (4-HNE), among them, is believed to be largely responsible for cytopathological effects observed during oxidative stress in vivo and has achieved the status of one of the best recognized and most studied of the cytotoxic products of lipid peroxidation. Here, we reported that 4-HNE treatment may induce cell death in MG63 human osteosarcoma cells. The 4-HNE treatment could activate caspase-3 and alter the Bax/Bcl-2 apoptotic signaling. All these changes are due to the inhibition of AKT activity by 4-HNE treatment, and we also found that the p70S6K activity, downstream factors of AKT, was also blocked by 4-HNE. Our results revealed the molecular mechanism of how 4-HNE induces cell death in MG63 human osteosarcoma cells, which contributes to the clinical treatment of cancer therapy.

Topics: Aldehydes; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bone Neoplasms; Caspase 3; Cell Death; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Humans; Osteosarcoma; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

Normal and malignant cells of various origin differ in their sensitivity to oxidative stress. Therefore, we used normal and malignant mesenchymal cells--human osteosarcoma cells (HOS and 143B), human fibroblasts (WI38) and two primary cultures of normal human osteoblasts to test sensitivity to reactive aldehyde 4-hydroxynonenal (HNE), known as a second messenger of free radicals and a signaling molecule. Upon HNE-treatment, decrease in cell viability (by Trypan-blue), apoptosis induction (by TiterTACS TUNEL assay), HNE-protein binding (by HNE-His ELISA) were higher in malignant than in normal cells, while glutathione content was higher in normal cells. These results indicate that HNE affects the growth of malignant mesenchymal cells more than normal and that this effect was mainly related to lower glutathione concentration and higher binding of HNE to the cellular proteins. We thus assume that HNE and GSH homeostasis play an important role in the growth regulation of normal and malignant mesenchymal cells.

Topics: Aldehydes; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Survival; Fibroblasts; Humans; Mesoderm; Neoplasm Proteins; Osteosarcoma; Proteins; Reference Values