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Renal cell carcinoma (RCC) is one of the most lethal urological cancers, highly resistant to chemo and radiotherapy. Obesity and smoking are the best-known risk factors of RCC, both related to oxidative stress presence, suggesting a significant role in RCC development and maintenance. Surgical resection is the treatment of choice for localized RCC; however, this neoplasia is hardly diagnosable at its initial stages, occurring commonly in late phases and even when metastasis is already present. Systemic therapies are the option against RCC in these more advanced stages, such as cytokine therapy or a combination of tyrosine kinase inhibitors with immunotherapies; nevertheless, these strategies are still insufficient. A field poorly analyzed in this neoplasia is the status of cell signaling pathways sensible to the redox state, which have been associated with the development and maintenance of RCC. This review focuses on alterations reported in the following redox-sensitive molecules and signaling pathways in RCC: mitogen-activated protein kinases, protein kinase B (AKT)/tuberous sclerosis complex 2/mammalian target of rapamycin C1, AKT/glycogen synthase kinase 3/β-catenin, nuclear factor κB/inhibitor of κB/epidermal growth factor receptor, and protein kinase Cζ/cut-like homeodomain protein/factor inhibiting hypoxia-inducible factor (HIF)/HIF as potential targets for redox therapy.

Quinolinic acid (QUIN) is an excitotoxic and pro-oxidant molecule used in the study of neurodegenerative disorders because it reproduces certain biochemical characteristics present in these diseases. The use of antioxidant molecules in the QUIN model reduces cellular damage through the nuclear factor erythroid 2-related to factor 2 (Nrf2) pathway. The Nrf2 transcription factor is considered the master regulator of antioxidant genes expression, and its activation occurs by an increase in the reactive oxygen species (ROS) levels or in the presence of electrophilic compounds. However, Nrf2 activation also occurs in an oxidative stress-independent process caused by the disruption of the Keap1-Nrf2 complex by the direct interaction of Keap1 with certain proteins, such as DPP3 and p62. The aim of this study was to evaluate the effect of QUIN on Nrf2 activation over short periods of time. QUIN administration increased Nrf2 activation at 30 min in the striatum without increasing ROS production or modifying the redox cellular state. Moreover, QUIN increased Keap1 and Nrf2 nuclear levels and increased the protein-protein interaction between Keap1 and DPP3 and Keap1 and p62 30 min after QUIN administration. Finally, we found that Nrf2 activation primarily occurs in striatal neurons. Our results show that QUIN administration in vivo stimulates Nrf2 expression and activation in the absence of oxidative stress primarily in neurons and increases the interaction of p62 and DPP3 with Keap1, which could participate in Nrf2 activation.

Renal cell carcinoma (RCC) is the most common type of cancer of the adult kidney. It is generally asymptomatic even at advanced stages, so opportune diagnosis is rare, making it almost impossible to study this cancer at its early stages. RCC tumors induced by ferric nitrilotriacetate (FeNTA) in rats histologically correspond to the human clear cell RCC subtype (ccRCC) and the exposure to this carcinogen during either one or two months leads to different early stages of neoplastic development. High levels of nuclear factor kappa B (NF-κB) and epidermal growth factor receptor (EGFR) as well as low levels of NF-κB inhibitor alpha (IκBα) are frequent in human RCC, but their status in FeNTA-induced tumors and their evolution along renal carcinogenesis is unclear. On this basis, in the present study NF-κB, IκBα and EGFR behavior was analyzed at different stages of the experimental renal carcinogenesis model. Similar to patients with RCC, neoplastic tissue showed high levels of p65, one of the predominant subunits of NF-κB in ccRCC and of EGFR (protein and mRNA), as well as a decrease in the levels of NF-κB's main inhibitor, IκBα, resulting in a classic oncogenic combination. Conversely, different responses were observed at early stages of carcinogenesis. After one month of FeNTA-exposure, NF-κB activity and EGFR levels augmented; but unexpectedly, IκBα also did. While after two months, NF-κB activity diminished, but EGFR and IκBα levels remained elevated. In conclusion, FeNTA-induced tumors and RCC human neoplasms are analogues regarding to the classic NF-κB, IκBα and EGFR behavior, and distinctive non-conventional combination of changes is developed at each early stage studied. The results obtained suggest that the dysregulation of the analyzed molecules could be related to different signaling pathways and therefore, to particular effects depending on the phase of the carcinogenic process.

Renal cell carcinoma (RCC) is asymptomatic at early stages, and thus, initial diagnosis frequently occurs at advanced or even metastatic stages, leading to a high rate of mortality. Ferric nitrilotriacetate (FeNTA)-induced RCC model is a useful tool to analyze molecular events at different stages of the carcinogenesis process in vivo. MAPKs' alterations seem to play an important role in the development and maintenance of human RCC tumors. Based on the above, p38α/β/γ, JNK1/2, and ERK1/2 statuses were studied at early stages of FeNTA-induced renal carcinogenesis (1 and 2 months of carcinogen treatment) as well as in tumor tissue. MAPKs showed distinct response along carcinogenesis process, either as total proteins and/or as their phosphorylated forms. While the increase in total and phospho-p38α/β levels became lower as carcinogenesis progressed, p38γ overexpression grew. Instead, total JNK2 diminished, but JNK1 was elevated at all studied times, and p-JNK1 levels increased at early stages, but not in tumors. In contrast, p-JNK2 rose at 2 months of treatment and in tumor tissue. Increased levels of p-ERK1/2 were observed at all stages analyzed. Very interestingly, at 1 and 2 months of FeNTA treatment, no alterations in MAPKs were found in liver or lung, where no primary tumors are induced with the scheme of FeNTA administration followed here. In conclusion, MAPKs' behavior evolved differentially as renal carcinogenesis advanced, even among isoforms of the same family, but it did not change in other tissues. All this strongly suggests a role of these kinases in FeNTA-induced RCC tumor development and maintenance.