Oxidative Stress in PC and Carcinogenesis
Numerous epidemiological, experimental and clinical studies have provided supportive evidence that oxidative stress is associated with the development of PC. Oxidative stress, as is often found in malignancies, leads to continuous damage of critical cellular constituents (proteins, nucleotides, lipids and metabolites), and finally cells with potential impact on the whole organism. Figure 1 models the mechanisms of oxidative stress-induced macromolecular cellular dysfunctions and their potential effects in carcinogenesis.
Consequently, a cellular ROS-detoxifying system has evolved, which consists of a multilayered defense system of enzymatic (thioredoxin, perodoxins, catalase and superoxide-dismutase) and non-enzymatic antioxidants (GSH and possibly bilirubin and uric acid). Figures 1 and 2 represents a summary of various conditions in PC that can lead to ROS and the enzymatic and non-enzymatic scavenging mechanisms of ROS present in human cells. Compared with benign prostatic epithelium, protein expression of catalase and superoxide dismutase is reduced in human prostatic intraepithelial neoplasia or prostate adenocarcinoma. This shift in cellular redox state in both primary and metastatic PC has profound effects on cell molecules.
Oxidative Cellular Damage and its Procarcinogenic Effects
ROS oxidizes DNA bases leading to mutations and DNA hypermethylation. ROS lead to peroxide formation in membrane lipid molecules, thus altering the physicochemical properties of membranes, and damage membrane-bound proteins and other macromolecules. Moreover, ROS exert calamitous chemical effects on proteins that can cause total inactivity or altered activity in function. Virtually any protein containing cysteine, methionine, tyrosine, lysine, arginine, proline or threonine residue is prone to ROS damage forming sulfenic, sulfinic and sulfonic derivatives, dityrosine, and leading to carbonylation, an oxidative process that forms reactive ketones and aldehydes in proteins. Altered protein function modulates cell signaling and can activate target genes that promote survival, progression and metastasis. Many transcription factors involved in PC, such as NF-κB, AP-1, HIF-1 and p53, are redox-sensitive, and thiol oxidation of these proteins modulates their DNA-binding activity. Proteins such as TRX, p53, IκB, RAS, AKT and protein tyrosine phosphatases require ROS-induced modifications of cysteine residues to maintain regulatory function. Such modifications include reversible glutathionylation, disulfide formation and S-nitrosylation. Conversely, severe oxidative stress as seen in PC could promote detrimental types of modifications, which include most likely irreversible sulfenic, sulfonic and sulfinic modifications. In addition, oxidative modification of one of the partners involved in protein–protein interactions in signaling pathways may alter or prevent the functioning of the complex, such as is the case for ASK1-TRX, JNK-GST, p53-JNK and Nrf2-Keap1. Mild thiol oxidation of the PC tumor suppressors, lipid phosphatase and tensin homolog and phosphatase cdc25, leads to activation, whereas permanent oxidation inhibits their regulatory function. Finally, redox-mediated oxidation of proteins may increase or decrease the protein half-life with deleterious effects in the translational and the ubiquitin and proteosome machinery of the cell.
Taken together, oxidative stress may discombobulate the physiologically acting proteome of the cell and serve as a stimulus to trigger stress-response signal-transduction pathways as well as modulate processes favoring cell survival by activating continuous proliferation. Stress response mechanisms triggered and regulated by ROS include apoptosis and autophagy. Increased ROS formation exerts antiapoptotic functions, which may enable PC to progress. Autophagy, a non-apoptotic cell death event, also activated through ROS, is executed by lysosomal cysteine cathepsins. Cathepsins has a causal role in the initiation and progression of many cancers, including PC. Although cancer initiation is not clearly understood, during early stages of PC development these redox-regulated events may conceivably support tumorigenesis.