Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer
Nakamura H, Takada K, Arihara Y, Hayasaka N, Murase K, Iyama S, Kobune M, Miyanishi K and Kato J
The over-expression of six-transmembrane epithelial antigen of the prostate 1 (STEAP1) underlies the pathogenesis of a large subset of human cancers. Expressed on the cancer cell surface, STEAP1 is an attractive target for antibody-based therapy or immunotherapy. However, its role in modulating the pathophysiology of colorectal cancer (CRC) remains relatively unexplored. In this study, we first demonstrated that the STEAP1 transcript level was significantly higher in CRC tissues than in normal colonic tissues. Of note, STEAP1 expression negatively correlated with overall survival as determined from a publicly accessible gene expression profile data set. A loss-of-function approach in cultured CRC cell lines revealed that STEAP1 silencing suppressed cell growth and increased reactive oxygen species (ROS) production, followed by apoptosis, through an intrinsic pathway. Mechanistically, the inhibition of STEAP1 was associated with decreased expression of antioxidant molecules regulated by the transcription factor, nuclear erythroid 2-related factor (NRF2), in CRC cells. Taken together, we identified high STEAP1 transcript levels leading to reduced ROS production that prevented apoptosis via the NRF2 pathway in CRC cells as a pathological mechanism in CRC. This study highlights the STEAP1-NRF2 axis as a therapeutic target for CRC and its manipulation as a novel strategy to conquer CRC.
p62/SQSTM1 - steering the cell through health and disease
Sánchez-Martín P and Komatsu M
SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer. In this Review, we summarize current knowledge regarding regulation, post-translational modifications and functions of SQSTM1, as well as how they are dysregulated in various pathogenic contexts.
Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF-1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase-3 signaling pathway in small cell lung cancer
Jiang W, Meng L, Xu G, Lv C, Wang H, Tian H, Chen R, Jiao B, Wang B and Huang C
Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI-H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA and . Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells and by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future.
NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma
Yen CH and Hsiao HH
Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed.
Synthesis and biological evaluation of bifendate derivatives bearing acrylamide moiety as novel antioxidant agents
Gu X, Jiang Y, Chen J, Zhang Y, Guan M, Li X, Zhou Q, Lu Q, Qiu J and Yin X
Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against HO-induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity. Interestingly, the Nrf2 activating effect of 6e is achieved, at least partly, in Michael acceptor and Keap1-dependent manners. These results, together with the low intrinsic cytotoxicity, suggested that compound 6e might be a promising lead for the development of novel anti-oxidant agents to prevent diseases induced by oxidative stress.
Supplementation of p-coumaric acid exhibits chemopreventive effect via induction of Nrf2 in a short-term preclinical model of colon cancer
Sharma SH, Rajamanickam V and Nagarajan S
Suppression of colorectal cancer by means of chemoprevention is gaining great attention owing to promising outcomes with less adverse effects in preclinical and clinical trials. The present study aims to explore the mechanism of chemoprevention by p-coumaric acid (p-CA) in a short-term preclinical model of colon cancer. 1,2-dimethylhydrazine-administered rats supplemented with p-CA showed downregulation of the expression of colonic proteins, namely, cyclin B1, cdc2, and mdm2, which regulate cell cycle, and immediate early response genes, namely, c-fos, c-jun and c-myc, which regulate cell proliferation. Apoptosis induction was also observed in the colon of p-CA-supplemented rats as assessed by the Bax/Bcl-2 ratio. Immunohistochemistry, immunoblotting and real-time polymerase chain reaction analysis revealed that supplementation of p-CA improved the in-vivo detoxification potential by modulating the cytoplasmic-to-nuclear ratio of nuclear factor erythroid 2-related factor 2, favouring the induction of genes responsible for cytoprotection and detoxification. The outcome of these findings suggests that p-CA inhibited polyp formation by improving the process of detoxification and apoptosis in the colon of 1,2-dimethylhydrazine-administered rats.
Fumonisin B-induced oxidative stress triggers Nrf2-mediated antioxidant response in human hepatocellular carcinoma (HepG2) cells
Arumugam T, Pillay Y, Ghazi T, Nagiah S, Abdul NS and Chuturgoon AA
Fumonisin B (FB), a causative agent for animal-related mycotoxicoses, has been implicated in human and animal cancer. FB induces oxidative stress but the related survival responses are not well established. Central to this response is the transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The effects of FB on Nrf2-related survival responses in human hepatoma (HepG2) cells were investigated. HepG2 cells were treated with 200 μmol/l FB (IC-24 h). Cellular redox status was assessed via the quantification of intracellular reactive oxygen species (ROS), lipid peroxidation, protein oxidation and the antioxidant glutathione (GSH). The protein expression of oxidative stress and mitochondrial stress response proteins [Nrf2, phosphorylated-Nrf2 (pNrf2), superoxide dismutase 2 (SOD2), catalase (CAT), sirtuin 3 (Sirt 3) and Lon-protease 1 (Lon-P1)] were quantified by western blotting, while gene expression levels of SOD2, CAT and GPx were assessed using quantitative polymerase chain reaction (qPCR). Lastly, the fluorometric, JC-1 assay was used to determine mitochondrial polarisation. FB significantly increased ROS (p ≤ 0.001), and induced lipid peroxidation (p < 0.05) and protein carbonylation (p ≤ 0.001), which corresponded with the increase in GSH levels (p < 0.05). A significant increase in pNrf2, SOD2, SOD2, CAT (p < 0.05), CAT (p ≤ 0.01) and GPx (p ≤ 0.001) expression was observed; however, total Nrf2 (p > 0.05) was reduced. There was also a minor reduction in the mitochondrial membrane potential of HepG2 cells (p < 0.05); however, the expression of Sirt 3 and Lon-P1 (p ≤ 0.001) were upregulated. Exposure to FB induced oxidative stress in HepG2 cells and initiated Nrf2-regulated transcription of antioxidants.
Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus
Fu J, Xiong Z, Huang C, Li J, Yang W, Han Y, Paiboonrungruan C, Major MB, Chen K, Kang X and Chen XL
Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the gene and genes in the same pathway (Nrf2, Keap1, K5Cre;Pkm2;Keap1, and wild-type) and analyzed for metabolomic profiles, Nrf2 ChIP-Seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 () was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype , and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2 ESCC in humans.
PPARγ maintains the metabolic heterogeneity and homeostasis of renal tubules
Lyu Z, Mao Z, Li Q, Xia Y, Liu Y, He Q, Wang Y, Zhao H, Lu Z and Zhou Q
The renal tubules, which have distant metabolic features and functions in different segments, reabsorb >99% of approximately 180 l of water and 25,000 mmol of Na  daily. Defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined.
Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer
Cai MC, Chen M, Ma P, Wu J, Lu H, Zhang S, Liu J, Zhao X, Zhuang G, Yu Z and Fu Y
Somatic KEAP1-NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2-mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2-mutant lung cancer presented APOBEC-mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune-cell infiltrates. Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single-sample prediction allowed for de novo identification of KEAP1/NRF2-active tumors within KEAP1/NRF2-wild-type samples. Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1-NRF2 pathway activation. This article is protected by copyright. All rights reserved.
Cisplatin Loaded Multiwalled Carbon Nanotubes Induce Resistance in Triple Negative Breast Cancer Cells
Badea MA, Prodana M, Dinischiotu A, Crihana C, Ionita D and Balas M
In this paper we developed a method for multiwalled carbon nanotubes (MWCNTs) use as carriers for a drug based on platinum in breast cancer therapy. The method of functionalization involves the carboxyl functionalization of nanotubes and encapsulation of cisplatin (CDDP) into MWCNTs. The biological properties of MWCNTs loaded with CDDP (MWCNT-COOH-CDDP) and of individual components MWCNT-COOH and free CDDP were evaluated on MDA-MB-231 cells. Various concentrations of CDDP (0.316⁻2.52 µg/mL) and MWCNTs (0.5⁻4 µg/mL) were applied on cells for 24 and 48 h. Only at high doses of CDDP (1.26 and 2.52 µg/mL) and MWCNT-COOH-CDDP (2 and 4 µg/mL) cell morphological changes were observed. The cellular viability decreased only with approx. 40% after 48 h of exposure to 2.52 µg/mL CDDP and 4 µg/mL MWCNT-COOH-CDDP despite the high reactive oxygen species (ROS) production induced by MWCNTs starting with 24 h. After 48 h, ROS level dropped as a result of the antioxidant defence activation. We also found a significant decrease of caspase-3 and p53 expression after 48 h, accompanied by a down-regulation of NF-κB in cells exposed to MWCNT-COOH-CDDP system which promotes apoptosis escape and thus failing to overcome the triple negative breast cancer (TNBC) cells resistance.
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) inhibition, An Emerging Strategy in Cancer Therapy
Jiang Z, Lu M and You QD
Nrf2 is a pleiotropic transcription factor, especially for its complex and dual effects in cancer. With the continuous growing research of the new regulatory modes and new functions of Nrf2 tumor promoting effects of Nrf2 in malignant transformed tumors has become increasingly clear. Accumulating evidence has established that Nrf2 contributes to the whole process of pathogenesis, progression, metastasis and prognosis of cancer, and Nrf2 could be a promising target in cancer therapy. However, the development of Nrf2 inhibitor is still limited. In this perspective, we will briefly describe the biological function and modulating network of Nrf2, stress its oncogenic role and point out possible ways to inhibit Nrf2, as well as summarize the reported Nrf2 inhibitors.
Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers
Soundararajan P and Kim JS
Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.
Reactive Oxygen Species as Regulators of MDSC-Mediated Immune Suppression
Ohl K and Tenbrock K
Reactive oxygen species (ROS) molecules are implicated in signal transduction pathways and thereby control a range of biological activities. Immune cells are constantly confronted with ROS molecules under both physiologic and pathogenic conditions. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive, immature myeloid cells and serve as major regulators of pathogenic and inflammatory immune responses. In addition to their own release of ROS, MDSCs often arise in oxidative-stress prone environments such as in tumors or during inflammation and infection. This evidently close relationship between MDSCs and ROS prompted us to summarize what is currently known about ROS signaling within MDSCs and to elucidate how MDSCs use ROS to modulate other immune cells. ROS not only activate anti-oxidative pathways but also induce transcriptional programs that regulate the fate and function of MDSCs. Furthermore, MDSCs release ROS molecules as part of a major mechanism to suppress T cell responses. Targeting redox-regulation of MDSCs thus presents a promising approach to cancer therapy and the role of redox-signaling in MDSCs in other disease states such as infection, inflammation and autoimmunity would appear to be well worth investigating.
The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice
Saito P, Melo CPB, Martinez RM, Fattori V, Cezar TLC, Pinto IC, Bussmann AJC, Vignoli JA, Georgetti SR, Baracat MM, Verri WA and Casagrande R
UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of inflammation. However, the therapeutic potential of RvD1 in UVB skin inflammation remains undetermined, which was, therefore, the aim of the present study. The intraperitoneal treatment with RvD1 (3-100 ng/mouse) reduced UVB irradiation-induced skin edema, myeloperoxidase activity, matrix metalloproteinase 9 activity, and reduced glutathione depletion with consistent effects observed with the dose of 30 ng/mouse, which was selected to the following experiments. RvD1 inhibited UVB reduction of catalase activity, and hydroperoxide formation, superoxide anion production, and gp91phox mRNA expression. RvD1 also increased the Nrf2 and its downstream targets NQO1 and HO-1 mRNA expression. Regarding cytokines, RvD1 inhibited UVB-induced production of IL-1β, IL-6, IL-33, TNF-α, TGF-β, and IL-10. These immuno-biochemical alterations by RvD1 treatment had as consequence the reduction of UVB-induced epidermal thickness, sunburn and mast cell counts, and collagen degradation. Therefore, RvD1 inhibited UVB-induced skin oxidative stress and inflammation, rendering this resolving lipid mediator as a promising therapeutic agent.

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