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Oxidative stress-related aging: A role for prostate cancer?

Prostate cancer has the highest prevalence of any non-cutaneous cancer in the human body and essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. Aging, considered as an impairment of body functions over time, caused by the accumulation of molecular damage in DNA, proteins and lipids, is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging. The aging damage may eventually appear in age-related health issues, which have a significant impact on the independence, general well-being and morbidity of the elderly. The association of aging with prostate cancer is undisputable as well as the association of aging with oxidative stress. Nevertheless, supportive evidence linking an increase in oxidative stress with prostate cancer is still scarce. This review is a comprehensive, literature-based analysis of the association of human prostate cancer with oxidative stress. The objective was to examine the involvement of reactive oxygen species in the mechanisms of prostatic carcinogenesis since the understanding of risk factors for prostate cancer has practical importance for public health, genetic and nutritional education, and chemoprevention.

Nrf2 and NF-κB and Their Concerted Modulation in Cancer Pathogenesis and Progression

Reactive oxygen species, produced by oxidative stress, are implicated in the initiation, promotion, and malignant conversion of carcinogenesis through activation/suppression of redox-sensitive transcription factors. NF-E2-related factor 2 (Nrf2) encodes for antioxidant and general cytoprotection genes, while NF-κB regulates the expression of pro-inflammatory genes. A variety of anti-inflammatory or anti-carcinogenic phyto-chemicals suppress NF-κB signalling and activate the Nrf2-ARE pathway. In this review we consider the role of Nrf2 and NF-κB in cancer pathogenesis and progression, focusing on their concerted modulation and potential cross-talk.

Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

α-Tocopheryl succinate (α-TOS) inhibits oxidative phosphorylation at the level of mitochondrial complex I and II, thus promoting cancer cell death through mitochondrial reactive oxygen species (ROS) generation. Redox imbalance activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor involved in cell protection and detoxification responses. Here we examined the involvement of heme oxygenase-1 (HO-1) in the regulation of nuclear factor κB (NF-κB) signaling by short exposure to α-TOS in prostate cancer cells. A short-term (4 h) exposure to α-TOS causes a significant reduction in cell viability (76%±9%) and a moderate rise in ROS production (113%±8%). α-TOS alters glutathione (GSH) homeostasis by inducing a biphasic effect, i.e., an early (1 h) decrease in intracellular GSH content (56%±20%) followed by a threefold rise at 4 h. α-TOS increases nuclear translocation and electrophile-responsive/antioxidant-responsive elements binding activity of Nrf2, resulting in up-regulation of downstream genes cystine-glutamic acid exchange transporter and HO-1, while decreasing NF-κB nuclear translocation. This effect is suppressed by the pharmacological inhibition of HO-1 and mimicked by the end-products of HO activity, i.e., bilirubin and carbon monoxide. Results suggest a little understood mechanism for α-TOS-induced inhibition of NF-κB nuclear translocation due to HO-1 up-regulation.

Focus on cyclo(His-Pro): history and perspectives as antioxidant peptide

Summary.Cyclo(His-Pro) is an endogenous cyclic dipeptide structurally related to tyreotropin-releasing hormone that was originally discovered in brain. In the central nervous system it has been described to exert multiple biological activities, which seem to be related to a presynaptic dopaminergic mechanism and include among the others a leptin-like function. It can be found in several body fluids and in the gastrointestinal tract where it has been suggested to act as a gut peptide with influence on the entero-insular axis. The oral administration of cyclo(His-Pro) and zinc was described to improve with a synergistic mechanism the glycaemic control in diabetes.The most intriguing function of this cyclic dipeptide is related with its neuroprotective role that was first reported in traumatic injuries of the spinal cord, and then confirmed in other models of experimental injuries of the nervous system. The mechanism that lies behind the neuroprotective activity of cyclo(His-Pro) remain poorly understood. Recent in vitro studies on rat pheochromocytoma PC12 cells have shown that it is a protective factor against stress stimuli and there is early pre-clinical evidence strongly suggesting that it enhances the expression of small heat shock proteins and antioxidant protection at the cellular level.Future research is underway to better characterize the possible use of this cyclic dipeptide in the therapy of neurodegenerative and metabolic disorders.

Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling.

Paraquat (1,1′‐dimethyl‐4,4′‐bipyridinium), a widely used non‐selective herbicide, is a redox cycling agent with adverse effects on dopamine systems. Epidemiological data have shown that exposure to paraquat is one of the several risk factors for Parkinson’s disease. We have already shown that cyclo(His‐Pro), an endogenous cyclic dipeptide produced by the cleavage of the thyrotropin releasing hormone, has a cytoprotective effect through a mechanism involving Nrf2 activation that decreases production of reactive oxygen species and increases glutathione synthesis. Using primary neuronal cultures and PC12 cells as targets of paraquat neurotoxicity, we addressed whether and how cyclo(His‐Pro) causes cellular protective response against paraquat‐mediated cell death. We found that cyclo(His‐Pro) attenuated reactive oxygen species production, and prevented glutathione depletion by up‐regulating Nrf2 gene expression, triggering its nuclear accumulation and activating the expression of heme oxygenase1. These protective effects were abolished by RNA interference‐mediated Nrf2 knock down whereas were unaffected by RNA interference‐mediated Keap1 knock down. Inhibition of heme oxygenase activity decreased cyclo(His‐Pro)‐induced neuroprotection. These results suggest that cyclo(His‐Pro), acting as a selective activator of the brain modulable Nrf2 pathway, may be a promising candidate as neuroprotective agent that act through induction of phase II genes.

Cyclo(His-Pro) exerts anti-inflammatory effects by modulating NF-κB and Nrf2 signalling.

Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts oxidative damage protection by selectively activating the transcription factor Nrf2 signalling pathway. Given the existence of a tight interplay of the Nrf2/NF-κB systems and that the pro-inflammatory response is governed by transcription factor NF-κB, here we sought to investigate whether and how cyclo(His-Pro) interferes with the cross-talk between the antioxidant Nrf2/heme oxygenase-1 and the pro-inflammatory NF-κB pathways. By knocking down the Nrf2 gene, we confirmed that cyclo(His-Pro) inhibits NF-κB nuclear accumulation induced by paraquat in rat pheochromocytoma PC12 cells via the Nrf2/heme oxygenase-1 pathway. The protection required functional heme oxygenase-1 activity, since zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, prevented NF-κB inhibition, and the presence of exogenous carbon monoxide and bilirubin afforded cytoprotection against paraquat-induced toxicity by preventing NF-κB activation. Cyclooxygenase-2 and matrix metalloproteinase 3, two gene products governed by NF-κB, were down-regulated by cyclo(His-Pro) and up-regulated in heme oxygenase-1 knock-down cells. We validated the general mechanism underlying the anti-inflammatory effects by treating PC12 and murine microglial BV2 cells with different pro-inflammatory agents. Finally, cyclo(His-Pro) reduced 12-otetradecanoylphorbol-13-acetate-induced oedema in mouse ear inflammation model. Results, by showing that cyclo(His-pro) suppresses the pro-inflammatory NF-κB signalling via the Nrf2-mediated heme oxygenase-1 activation, contribute to the understanding of essential cellular pathways and allow the proposal of cyclo(His-Pro) as an in vivo anti-inflammatory compound.

Cyclic dipeptides: from bugs to brain

Cyclic dipeptides (CDPs) are a group of hormone-like molecules that are evolutionarily conserved from bacteria to humans. In bacteria, CDPs are used in quorum sensing (QS) to communicate information about population size and to regulate a behavioural switch from symbiosis with their host to virulence. In mammals, CDPs have been shown to act on glial cells (macrophage-like cells) to control a conceptually homologous behavioural switch between homeostatic and inflammatory modes, with implications for the control of neurodegenerative disease. Here we argue that, because of their capacity to regulate inflammation via glial cells and induce a protective response in neuronal cells, CDPs have potential therapeutic utility in an array of inflammatory diseases.

Differential involvement of reactive oxygen species and nucleoside transporters in cytotoxicity induced by two adenosine analogues in human prostate cancer cells.

Elevated levels of cellular oxidative stress represent a specific vulnerability of malignant cells and exposure to cytotoxic drugs is known to induce oxidative stress in cancer cells. The effects of two adenosine analogues, 2‐chloroadenosine and 2‐chlorodeoxyadenosine, were investigated to assess their mechanism of action in prostate cancer cells.

Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity.

Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2-NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions.

A Novel Role for Tm7sf2 Gene in Regulating TNFα Expression

We have explored the role of Tm7sf2 gene, which codifies for 3β-hydroxysterol Δ14-reductase, an endoplasmic reticulum resident protein, in the sensitivity to endoplasmic reticulum stress and in the resulting inflammatory response. We used mouse embryonic fibroblasts, derived from Tm7sf2+/+ and Tm7sf2−/− mice, to determine the in vitro effects of thapsigargin on NF-κB activation. Our results show that the Tm7sf2 gene controls the launch of the unfolded protein response and presides an anti-inflammatory loop thus its absence correlates with NF-κB activation and TNFα up-regulation. Our data also show that Tm7sf2 gene regulates liver X receptor activation and its absence inhibits LXR signalling. By expressing the hTm7sf2 gene in KO MEFs and observing a reduced NF-κB activation, we have confirmed that Tm7sf2 gene is linked to NF-κB activation. Finally we used genetically modified mice in an in vivo model of ER stress and of inflammation. Our results show a significant increase in renal TNFα expression after tunicamycin exposure and in the oedematogenic response in Tm7sf2−/− mice. In conclusion, we have shown that the Tm7sf2 gene, to date involved only in cholesterol biosynthesis, also controls an anti-inflammatory loop thereby confirming the existence of cross talk between metabolic pathways and inflammatory response.