Cellular transformation is a complex process involving genetic alterations associated with multiple signaling pathways. Development of a transformation model using defined genetic elements has provided an opportunity to elucidate the role of oncogenes and tumor suppressor genes in the initiation and development of
ovarian cancer. To study the cellular and molecular mechanisms of Ras-mediated oncogenic transformation of ovarian epithelial cells, we used a proteomic approach involving two-dimensional electrophoresis and mass spectrometry to profile two ovarian epithelial cell lines, one immortalized with SV40 T/
t antigens and the human catalytic subunit of
telomerase and the other transformed with an additional oncogenic ras(V12) allele. Of approximately 2200 observed
protein spots, we have identified >30
protein targets that showed significant changes between the immortalized and transformed cell lines using
peptide mass fingerprinting. Among these identified targets, one most notable group of
proteins altered significantly consists of
enzymes involved in cellular redox balance. Detailed analysis of these
protein targets suggests that activation of Ras-signaling pathways increases the threshold of reactive oxidative species (ROS) tolerance by up-regulating the overall
antioxidant capacity of cells, especially in mitochondria. This enhanced
antioxidant capacity protects the transformed cells from high levels of ROS associated with the uncontrolled growth potential of
tumor cells. It is conceivable that an enhanced antioxidation capability may constitute a common mechanism for
tumor cells to evade apoptosis induced by oxidative stresses at high ROS levels.