Oxidative stress in prostate cancer

Abstract

As prostate cancer and aberrant changes in reactive oxygen species (ROS) become more common with aging, ROS signaling may play an important role in the development and progression of this malignancy. Increased ROS, otherwise known as oxidative stress, is a result of either increased ROS generation or a loss of antioxidant defense mechanisms. Oxidative stress is associated with several pathological conditions including inflammation and infection. ROS are products of normal cellular metabolism and play vital roles in stimulation of signaling pathways in response to changing intra- and extracellular environmental conditions. Chronic increases in ROS over time are known to induce somatic mutations and neoplastic transformation. In this review we summarize the causes for increased ROS generation and its potential role in etiology and progression of prostate cancer.

Fig. 1. Mechanisms of ROS production, and cellular response to ROS in prostate cells

Many factors both intrinsic to the cells and to external environment can lead to higher ROS production in the prostate. Increased ROS levels can lead to prostate dysfunction which in turn leads to more ROS production. An enzymatic or non-enzymatic antioxidant defense system counteracts and regulates ROS level to maintain physiological homeostasis. Lowering ROS level below the homeostatic point may interrupt proliferation and host defense system, while accumulative ROS in prostate can alter normal functioning of the prostate leading to low antioxidant level [by disrupting Nrf2-antioxidant response element axis(ARE)], increase mtDNA mutation and aggressive phenotypes, and caused DNA damage.

Fig. 2. Metabolic switch and mitochondrial DNA (mtDNA) mutation accelerate ROS generation in prostate cancer

Alterations in metabolism from high citrate to low citrate production, and truncated oxidative phosphorylation (OXPHOS) to complete OXPHOS status during the malignant transformation of prostate lead to complete citrate oxidation, and more ROS generation in prostate cancer cells. Similarly, homoplasmic mtDNA point mutations and mtDNA instability with time and age cause mitochondrial hyper mutagenesis. This event causes enormous amount of ROS generation, and we hypothesize that it might lead to impaired electron transport chain (ETC) resulting in decreased citrate production, which in consequence generates more ROS in prostate cancer cells. Once enhanced ROS generation is started, subsequent activation of signaling pathways and redox-sensitive transcription factors like HIF-1α, Ets, Snail has been shown to play a major role in progression and metastasis of the cancer cells.

Fig. 3. Activation of reactive oxygen species (ROS) generation by assembly of phox regulatory protein

(a). Activation of Nox enzyme (equivalent to gp91phox component of phagocytes) system results in assembly of cytosolic regulatory proteins (p40phox, p47phox and p67phox) with flavocytochrome b558 (f.cyt b558; comprised of membrane associated catalytic subunit Nox plus p22phox). These trigger nucleotide exchange protein that activates the GTPase RAC. Protein kinases catalyse many phosphorylation events and allowing p47phox binding to lipid along with p67 phox and p40phox. Activation of exchange factors triggers GTP binding, resulting in conformational change in RAC that promote dissociation from RhoGDI, and promote RAC-GTP binding to p67phox, helping to assemble the active complex. (b). schematic illustrating the role of NAD(P)H oxidase system in prostate cancer cells. In case of prostate cancer cells, NAD(P)H oxidase1 (Nox1), Nox2, Nox3 and Nox4 are similar in size to gp91phox, while Nox5 consists of an additional amino-terminal calcium binding domain, and independent of p22phox requirement for their activity. We hypothesize that increased ROS generation as a result of activation of NAD(P)H oxidase system(s) in prostate cancer cells mediates several signaling pathways critical for growth and could potentially regulate various phenotypic features of cancer cells. Dashed lines indicate possible mechanisms of action.