Many transcription factors that include HIF-1, NF-plays a vital role in cell transformation [36]

Many transcription factors that include HIF-1, NF-plays a vital role in cell transformation [36]. discusses the generation and biological roles of ROS in PCa and provides new strategies based on the regulation of ROS for the treatment of PCa. 1. Introduction PCa has the highest prevalence for males in Europe as well as America and is also the second leading cause of cancer-related deaths for males [1]. In the year 2020, approximately 1,920,000 new cases of PCa are expected to be diagnosed, of which 33,000 may die [2]. The incidence of PCa has increased in recent years, notably in developing countries, which is strongly associated with economic development and lifestyle [2C5]. Multiple processes are involved in malignant transformation of prostate cells, initiating as prostatic intraepithelial neoplasia (PIN) followed by localized PCa. The early stages of PCa progression are treated by radical prostatectomy and localized radiation [1]. Once these therapies Salmefamol fail, the standard treatment for late-stage PCa is aimed at preventing androgen binding to AR (androgen deprivation therapy, ADT) or inhibiting AR activity directly (antiandrogens). This strategy comes from the fact that the primary prostate tumor is mostly made up of Androgen Receptor-positive (AR+) cancer cells, which are initially androgen-dependent. Despite responding to ATD during the first 14-20 months, almost all patients acquire Salmefamol resistance and progress into castration-resistant prostate cancer (CRPC) with primary metastasis of the lymph nodes or bones [6]; it is often fatal, and the overall survival (OS) is relatively low. Therefore, the treatment of PCa remains a formidable challenge and enigma. ROS are a class of highly reactive, oxygen-containing molecules mainly including superoxide anion, hydrogen peroxide, hydroxyl radicals, and singlet oxygen [7], which cannot be detected directly in human specimens due to their short half-lives [8]. Hydroxyl radical (OH?) is the most unstable and reacts fleetly with adjacent biomolecules. Additionally, hydrogen peroxide (H2O2), as the major species of ROS, can cross the cell membranes and exert effects beyond the cell limits [9]. Intracellular ROS levels are tightly dependent on the various synthesis and degradation pathways. Maintenance of ROS at physiological levels is crucial to redox regulation involving repair, survival, and differentiation [7, 10]. However, either excessive generation of ROS or a decrease in the free radical scavenging system may increase ROS levels, thus inducing oxidative stress that acts as an etiological factor for wide varieties of pathologies, such as diabetes, myocardial injury, and cancer [4, 10]. As two-faced molecules, ROS have either beneficial or deleterious effects on PCa cells. Many experimental and clinical results have demonstrated that higher levels of ROS, particularly free radicals, can cause oxidative damages in DNA, proteins, and lipids, further contributing to the pathogenesis and the progression of PCa [11, 12]. Thus, it is reasonable to anticipate that the use of antioxidants has the potential to prevent and treat prostate carcinogenesis by eliminating ROS and oxidative stress. Besides, further accumulation of ROS could disturb normal cellular processes, Rabbit polyclonal to AMOTL1 eventually resulting in cell death [13, 14]. This current review aims to focus on proposed mechanisms by which ROS either promote or inhibit the progression of PCa and provides clues for anticancer therapies based on redox regulation. With respect to the extensive pleiotropy of ROS, the emerging field of redox medicine has received increasing attention in recent years. Therefore, further studies are required to elucidate the relationship between ROS and PCa. 2. Sources of Intracellular ROS in PCa Both endogenous and exogenous sources promote the generation of intracellular ROS. Higher levels of basal ROS in PCa cells result from mitochondria dysfunction, increased p66Shc, glucose metabolism Salmefamol (Warburg effect), and the activation of enzymes including NADPH oxidases, xanthine oxidases, and cytochrome P450 [15]. In the following paragraphs, we especially pay attention to mitochondria dysfunction, NADPH oxidases, and p66Shc activation, which are significant contributors of endogenous ROS in.