Apoptosis Oxidative Stress and BPH

An alternative mechanism for BPH may be related to metabolic disturbances. Obesity and elevated fasting glucose are components of the metabolic syndrome [61] [ Both the obesity and the metabolic syndrome are associated with systemic inflammation and oxidative stress [62]. Inflammation has been previously implicated as a primary stimulus for prostate carcinogenesis [63], and in the same way, it is possible that BPH represents an alternate, nonmalignant pathway of unregulated prostate growth promoted by oxidative stress, inflammatory mediators, and IGFs [64] [ Indeed, the analyses of surgical specimens have shown that BPH is usually associated with inflammation and that the extent and severity of the inflammation correspond to the amount of prostate enlargement [65] .

BPH is a phenomenon characterized by an age-dependent increase in the volume of the prostate throughout the entire life of a man. The growth and involution of the prostate depend on the quantitative relationship between the rate of cell proliferation and cell death. Most previous studies have focused on proliferative and apop-totic rates in benign hyperplastic human prostates. Siegfried et al. [66] reported that there is an increase in the proliferation rate and decrease in the apoptosis rate in benign hyperplastic prostatic tissue. Therefore, the authors suggested that the growth of the aging prostate results from this disturbance in the balance between cell proliferation and apoptosis. Claus et al. [67] studied the apoptotic and proliferative rates in the epithelium and the stroma of BPH. They also demonstrated the apoptotic and proliferative rate in the epithelium of normal prostatic tissue. Interestingly, the results of this study indicate a decrease in the apoptotic rate in the stroma of BPH which may explain the enlargement of the prostatic tissue [ 68]. Apoptosis, also known as programmed cell death, plays an important role in all stages of an organism's development. While there are controversies in the literature regarding the role of apoptosis in aging, age-associated increases in apoptosis have been observed in several physiological systems, including the human immune system, human hair follicle, and rat skeletal muscle [69] [ Apoptotic cell death is executed via two major signaling pathways, the intrinsic and extrinsic pathways, in either caspase-dependent or caspase-independent manners [ 70]. The intrinsic pathway involves the induction of various protein responses, such as posttranslational modifications, conformational changes, and interorganelle translocation of specific proteins. These responses can produce an alteration in mitochondrial membrane potential and the release of apoptogenic factors, such as cytochrome c and apoptosis-inducing factor, from the mitochondria to the cytoplasm. A cascade of downstream signals, including caspases, is then stimulated to orchestrate apoptotic responses. In contrast, the induction of apoptosis by extrinsic pathways requires binding of ligands to membrane receptors and recruitment of cytosolic adaptor proteins, which will, in turn, activate a series of initiator and effector caspases. It has been clearly established that ROS and ROS-modulated molecules participate in both intrinsic and extrinsic apoptotic pathways [71] . Some well-known exogenous ROS-generating stressors, such as radiation, proinflammatory cytokine treatment, growth factor withdrawal, and physiological challenges, such as heat stress, can stimulate apoptosis [72, 73]. One example of oxidative stress involvement in the extrinsic apoptotic signaling pathways is the redox activation of the Mitogen-activated protein kinases (MAPK) cascade upon sustained oxidative stress. A novel protein in the mitogen-activated protein kinase-kinase-kinase family, known as apoptosis signal-regulating kinase 1 (ASK1), has recently been identified as a critical redox sensor in the MAPK pathway [74]. Thioredoxin, a small enzyme that participates in redox reactions, can have a negative regulatory influence on ASK1 and, subsequently, apoptosis. Oxida-tive stress-induced apoptosis can also be reduced by a dominant-negative mutation of ASK1 [75] . Another example involving the extrinsic apoptotic pathway is the down-regulation of signaling pathways associated with growth factor receptor stimulation in response to oxidative stress [76]. In the intrinsic apoptotic pathway, it has been shown that proteins in the mitochondrial permeability transition pore complex, which controls mitochondrial membrane potential, are the direct targets of ROS. These proteins include the adenine nucleotide translocator in the inner membrane, the voltage-dependent anion channel in the outer membrane, and cyclo-philin D at the matrix. Prooxidants capable of induction of mitochondrial permeability potential include not only chemicals, such as [eri-butyl hydroperoxide and diamide, but also lipid peroxidation products such as 4-hydroxynonenal. Moreover, it has been increasingly recognized that oxidative damage to organelles, such as lysosomes and endoplasmic reticulum, stimulates crosstalk between these organelles and mitochondria and induction of apoptosis via the intrinsic signaling pathway [77].

More importantly, recent studies on p66Shc redox protein may provide a link between oxidative stress-mediated apoptosis and biological aging [78]. The p66Shc redox protein is the third isoform discovered in the Shc protein family. This group of proteins was initially identified as signal transduction adapters involved in mutagenic signaling through Ras, a small GTP-binding protein. Evidence has suggested that p66Shc is an atypical signal transducer that can be regulated by oxidative stress and also plays a role in H2O2 generation [79]. While mice lacking p66Shc (p66Shc-/-) live 30% longer than the control animals, p66Shc-/- cells from knockout mice are resistant to ROS-induced apoptosis. Several lines of evidence indicate that p66Shc potentially acts at sites upstream of the mitochondrial permeability transition pore in oxidative stress-mediated apoptosis [80] .

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