C-Cbl contributes to the generation of reactive oxygen species and inhibits apoptosis in LNCaP cells / by Elsy Elias Rechdane.

Abstract

The proto-oncoprotein c-Cbl is an E3-ubiquitin ligase that can downregulate activated receptor tyrosine kinases, and interact with several signaling and adaptor molecules. This allows c-Cbl to influence several downstream signaling pathways. Recently, c-Cbl has been reported to play a protective role against apoptosis in a number of cells. It has also been reported to play a role in energy expenditure and mitochondrial oxidation of fatty acids. Cbl deficiency in mice was found to be correlated with higher AMPK activation, as well as phosphorylation of Acetyl-Coenzyme A carboxylase (ACC), which inhibits its activity. More recently, a higher rate of expression of c-Cbl was reported in a number of tumors that exhibit high levels of oxidative stress. The level of c-Cbl expression was also found to increases with the degree of severity of the cancer, as well as the level of the reactive oxygen species (ROS). Since malignant cells are resistant to high levels of oxidative stress, and since c-Cbl has been attributed a protective role in other cells, we propose that it could play a similar role in cancer cells, also through interacting with signaling pathways. Furthermore, since c-Cbl has been shown to regulate metabolic pathways that result in ROS accumulation, we believe that c-Cbl is likely to play a role in the generation of ROS in malignant cells. Our work suggests a protective role for c-Cbl against oxidative stress in the lymph node carcinoma of the prostate (LNCaP) cell line, through the down-regulation of the p38MAPK pathway and the Akt pathway, and reveals the involvement of c-Cbl in ROS generation in LNCaP cells.