• MAT2A and MTAP synthetic lethality
• MAT2A-driven tumor progression
• MTAP-null cancers
• cancer cell metabolism
• methionine synthesis

• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Animals
• Methionine Adenosyltransferase/genetics
• Methionine Adenosyltransferase/metabolism
• Methionine Adenosyltransferase/antagonists & inhibitors
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Tumor Microenvironment
• Epigenesis, Genetic
• Transcription, Genetic
• Purine-Nucleoside Phosphorylase

Heme oxygenases (HOs) act on heme degradation to produce carbon monoxide (CO), free iron, ferritin, and biliverdin. Upregulation of cellular HO-1 levels is signature of oxidative stress for its downstream effects particularly under pro-oxidative status. Subcellular traffics of HO-1 to different organelles constitute a network of interactions compromising a variety of effectors such as pro-oxidants, ROS, mitochondrial enzymes, and nucleic transcription factors. Some of the compartmentalized HO-1 have been demonstrated as functioning in the progression of cancer. Emerging data show the multiple roles of HO-1 in tumorigenesis from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy. However, the role of HO-1 in tumorigenesis has not been systematically addressed. This review describes the crosstalk between HO-1 and oxidative stress, and following redox regulation in the tumorigenesis. HO-1-regulated signaling pathways are also summarized. This review aims to integrate basic information and current progress of HO-1 in cancer research in order to enhance the understandings and facilitate following studies.

• cancers
• heme oxygenase-1
• mitochondria
• nuclei
• reactive oxygen species
• subcellular localization

• HO-1
• Th2-related response
• atopic dermatitis
• miquelianin
• trimellitic anhydride

• NRF2 inhibitors
• NRF2-KEAP1
• cancer
• chemotherapy
• oxidative stress
• reactive oxygen species
• redox therapy

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ₂ as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ₂ during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ₂.

• 15-Deoxy-Δ12,14-prostaglandin J2
• MCF-7 cells
• NRF2
• VEGF
• angiogenesis
• breast cancer
• heme oxygenase-1

• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Cyclooxygenase 2/adverse effects
• Female
• Heme Oxygenase-1/metabolism
• Humans
• NF-E2-Related Factor 2/metabolism
• Prostaglandins/metabolism
• Transfection
• Up-Regulation
• Vascular Endothelial Growth Factor A/metabolism

• anti-inflammatory compound
• antioxidant
• foodstuff
• heme oxygenase-1
• medicinal herbs

• 2020R1A2C1004131, 2019R1F1A1051041 National Research Foundation of Korea

• KEAP1
• NRF2
• PRCC
• ccRCC
• kidney injury

• IG2019-23513 Associazione Italiana per la Ricerca sul Cancro

• NRF2
• breast cancer
• cancer
• cancer metabolism
• reactive species

Negative energy balance (NEB) during the perinatal period can affect dairy cow follicular development and reduce the fecundity. Non-esterified fatty acid (NEFA) concentration is elevated during NEB, and is known to be toxic for multiple cell types. In the ovary, NEB increased NEFA, and may influences follicular growth and development. However, the effect and mechanism of NEFA on granulosa cells (GCs) in vitro remains unknown. In this study, we found that NEFA dose-dependently induced apoptosis in primary cultured granulosa cells. Mechanistically, our data showed that NEFA significantly increased reactive oxygen species (ROS) levels, resulting in the activation of endoplasmic reticulum stress (ERS) and eventually cell apoptosis in GCs. Moreover, NEFA also increased the phosphorylation levels of ERK1/2 and p38MAPK pathways, upregulated the expression of p53 and potentially promoted its translocation to the nuclear, thus transcriptionally activated Bax, a downstream gene of this pathway. NEFA also promoted nuclear factor E2 (Nrf2) expression and its level in the nuclear. To elucidate the mechanism of NEFA action, N-acetyl-l-cysteine (NAC), a ROS scavenger was used to verify the role of ROS in NEFA induced apoptosis of GCs. NAC pretreatment reversed the NEFA-induced ERS-related protein and apoptosis-related protein levels. Meanwhile, NAC pretreatment also blocked the phosphorylation of ERK1/2 and p38 induced by NEFA, and the nucleation of Nrf2 and p53, suggesting that ROS plays a crucial role in regulating the NEFA-induced apoptosis of GCs. Together, these findings provide an improved understanding of the mechanisms underlying GCs apoptosis, which could potentially be useful for improving ovarian function.

• N-acetyl-L-cysteine
• ROS
• apoptosis
• granulosa cells
• non-esterified fatty acid

• Fish
• HO-1
• NRF2 and ATF4
• Oxidative stress
• PERK

• Animals
• Carps/physiology
• DNA, Complementary
• Fish Proteins/genetics
• Fish Proteins/metabolism
• Gene Expression Regulation
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress/physiology
• RNA, Messenger

Heme oxygenase-1 (HO-1) has antiinflammatory and antioxidant properties and is deemed as a tissue protector. However, effects of HO-1 in prostate cancer remain in controversy. We evaluated the role of HO-1 in prostate carcinoma in vitro and in vivo.

Overexpression of HO-1 did not affect prostate cell proliferation in the normal condition but enhanced cell proliferation under serum starvation. HO-1 overexpression enhanced cell invasion of PC-3 cells through epithelial–mesenchymal transition (EMT) induction, which was supported by increased Slug, N-cadherin, and vimentin expressions. In the xenograft animal study, HO-1 overexpression enhanced PC-3 cell tumor growth in vivo. HO-1 attenuated reactive oxygen species induced by H₂O₂ or pyocyanin treatment in PC-3 and DU145 cells. HO-1 further reduced PC-3 and DU145 cell apoptosis induced by H₂O₂ or serum starvation. Our results suggested that HO-1 was able to increase prostate carcinoma cell invasion in vitro and tumor growth in vivo. The EMT induction and antioxidant and antiapoptotic effects of HO-1 in the prostate carcinoma cells may be responsible for these findings.

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

• Clear cell renal cell carcinoma
• differentially expressed miRNAs
• survivability
• targets

• Adult
• Aged
• Biomarkers, Tumor
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/mortality
• Carcinoma, Renal Cell/pathology
• Carcinoma, Renal Cell/therapy
• Computational Biology/methods
• Databases, Nucleic Acid
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Molecular Sequence Annotation
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• RNA Interference
• RNA, Messenger/genetics

• HO-1
• Nrf2
• ROS
• immunohistochemistry
• prognosis

• ERK
• Nrf2
• ROS
• Raf-1
• metformin
• psoriasis

• CXCR3-B signals
• apoptosis
• breast cancer
• chemokine
• mechanism
• paeonol

Estrogen (17β-estradiol, E₂) undergoes oxidative metabolism by CYP1B1 to form 4-hydroxyestradiol (4-OHE₂), a putative carcinogenic metabolite of estrogen. Our previous study showed that 4-OHE₂-induced production of reactive oxygen species contributed to neoplastic transformation of human breast epithelial (MCF-10A) cells. In this study, 4-OHE₂, but not E₂, increased the expression of heme oxygenase-1 (HO-1), a sensor and regulator of oxidative stress, in MCF-10A cells. Silencing the HO-1 gene in MCF-10A cells suppressed 4-OHE₂-induced cell proliferation and transformation. In addition, subcutaneous administration of 4-OHE₂ markedly enhanced the growth of the MDA-MB-231 human breast cancer xenografts, which was retarded by zinc protoporphyrin, a pharmacological inhibitor of HO-1. 4-OHE₂-induced HO-1 expression was mediated by NF-E2-related factor 2 (Nrf2). We speculate that an electrophilic quinone formed as a consequence of oxidation of 4-OHE₂ binds directly to Kelch-like ECH-associated protein 1 (Keap1), an inhibitory protein that sequesters Nrf2 in the cytoplasm. This will diminish association between Nrf2 and Keap1. 4-OHE₂ failed to interrupt the interaction between Keap1 and Nrf2 and to induce HO-1 expression in Keap1-C273S or C288S mutant cells. Lano-LC-ESI-MS/MS analysis in MCF-10A-Keap1-WT cells which were treated with 4-OHE₂ revealed that the peptide fragment containing Cys288 gained a molecular mass of 287.15 Da, equivalent to the addition of a single molecule of 4-OHE₂-derived ortho-quinones.

• 4-hydroxyestradiol
• Nrf2
• breast cancer
• catechol estrogen
• heme oxygenase-1

• ER stress
• ERK pathway
• Heat shock response
• Hepatocellular Carcinoma (HCC)
• Hereditary tyrosinemia type 1
• Liver cancer
• MEK pathway
• Metabolic disease
• NTBC
• Nrf2
• Signaling pathways
• p21

Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti-tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) play a critical role in the growth and progression of renal cell carcinoma (RCC). Interestingly, the calcineurin inhibitor (CNI) cyclosporine A (CsA), an immunosuppressant used to prevent allograft rejection, can also increase the risk of RCC in transplant patients. We studied the potential role of c-Met signaling axis on CNI-induced renal tumor growth and tested the anti-tumor efficacy of HNK. Importantly, CNI treatment promoted c-Met induction and enhanced c-Met-induced Ras activation. We found that HNK treatment effectively down-regulated both c-Met phosphorylation and Ras activation in renal cancer cells. It inhibited the expression of both c-Met- and CNI-induced HO-1, and promoted cancer cell apoptosis. In vivo, HNK markedly inhibited CNI-induced renal tumor growth; and it decreased the expression of phospho-c-Met and HO-1 and reduced blood vessel density in tumor tissues. Our results suggest a novel mechanism(s) by which HNK exerts its anti-tumor activity through the inhibition of c-Met-Ras-HO-1 axis; and it can have significant therapeutic potential to prevent post-transplantation cancer in immunosuppressed patients.

Propoxur is considered a prime etiological suspect of increasing tumor incidence, but the role is still undefined. In this study, two human breast cancer cells lines, MCF-7 and MDA-MB-231 cells, were used as cell models. Cells were respectively treated with 0, 0.01, 1, or 100 μM propoxur. PD98059, a MEK inhibitor, was administered to block the ERK/MAPK pathway. Migration and reactive oxygen species were measured by wound healing and Transwell assays, and flow cytometry. Protein expression and subcellular location were detected by western blotting and immunofluorescence staining, respectively. Results showed that propoxur treatment enhanced cell migration and invasion in a dose-dependent manner, while MMP-2 expression, but not MMP-9, was significantly increased in two cell lines. Meanwhile, the treatment increased intracellular reactive oxygen species, Nrf2 expression and nuclear translocation, and ERK1/2 phosphorylation. Inversely, inhibition of ERK1/2 activation with PD98059 significantly attenuated propoxur-induced Nrf2 expression and nuclear translocation. Moreover, PD98059 suppressed propoxur-induced cell migration and invasion, and MMP-2 overexpression. Collectively, these results indicate that propoxur can trigger reactive oxygen species overproduction, further promoting breast cancer cell migration and invasion by regulating the ERK/Nrf2 signaling pathways.

• extracellular signal-regulated kinase 1/2
• matrix metalloproteinase
• nuclear factor E2-related factor 2
• propoxur

• Carcinoma
• Heme oxygenase-1
• Nerve growth factor
• Prognosis
• Stomach

• chronic pancreatitis
• pancreatic cancer precursor lesion
• oxidative stress
• tgf-β1
• proliferation
• pancreatic cancer

• Apoptosis/genetics
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Ki-67 Antigen/genetics
• Ki-67 Antigen/metabolism
• Mitogen-Activated Protein Kinases/metabolism
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress
• Pancreatic Ducts/metabolism
• Pancreatic Ducts/pathology
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Precancerous Conditions
• Protein Binding
• Signal Transduction
• Smad Proteins/metabolism
• Transforming Growth Factor beta1/antagonists & inhibitors
• Transforming Growth Factor beta1/metabolism
• Pancreatic Neoplasms

• Deutsche Forschungsgemeinschaft
• Lieselotte Beutel Stiftung

Trigonelline occurs in many dietary food plants and has been found to have anti-carcinogenic activity. Trigonelline is also found in coffee which is one of the most widely consumed beverages. Many epidemiological studies have reported that coffee consumption has an inverse relationship with the risk of cirrhosis or hepatocellular carcinoma. It would be interesting to investigate whether trigonelline is an ideal chemoprevent agent to prevent cancer progression.

The protein expression was performed by western blotting. The trigonelline content in snow pea (Pisum sativum) was analyzed by high-performance liquid chromatography (HPLC). The migratory activity of human hepatocarcinoma cells (Hep3B) was assessed by using a wound migration assay. The percentage of each phase in the cell cycle was analyzed on a FACScan flow cytometer. Gene expression was detected by real-time reverse transcriptase-polymerase chain reaction techniques. Native gel analysis was performed to analyze the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase.

According to the data of HPLC analysis, P. sativum, which is a popular vegetable, has relatively high content of trigonelline. Our findings suggest that trigonelline is an efficient compound for inhibiting Hep3B cell migration. Trigonelline inhibited the migration of hepatoma cells at concentrations of 75–100 µM without affecting proliferation. Raf/ERK/Nrf2 protein levels and further downstream antioxidative enzymes activity, such as SOD, catalase, and glutathione peroxidase, significantly decreased after treatment with 100 µM of trigonelline for 24 h. The migration inhibition of trigonelline is also related to its ability to regulate the matrix metalloproteinases 7 (MMP-7) gene expression.

In this study, protein kinase Cα (PKCα) and Raf/ERK/Nrf2 signaling pathway and MMP-7 gene expression were involved in the trigonelline-mediated migration inhibition of Hep3B cells. We also demonstrated that trigonelline inhibits Hep3B cell migration through downregulation of nuclear factor E2-related factor 2–dependent antioxidant enzymes activity. This study analyzed the trigonelline content in a popular vegetable, snow pea, as a representative proof to prove that trigonelline is often found in the daily intake of food. Our finding suggested that trigonelline should be a useful chemopreventive agent derived from the daily intake of food to prevent cancer progression.

• MMP-7
• Pisum sativum
• Raf/ERK/Nrf2 signaling pathway
• chemotherapeutic agent
• hepatocarcinoma Hep3B cells
• migration
• trigonelline

• Angiogenesis
• Carbon monoxide
• HO-1 inhibitors
• MicroRNAs
• Tumorigenesis

• ER stress
• HO-1
• Hepatoma
• Hereditary tyrosinemia type 1 (HT1)
• Liver dysfunction
• Metabolic diseases

We analyzed the expression of heme oxygenase-1 (HO-1) in patients undergoing radical nephrectomy for advanced clear cell renal cell carcinoma (CC-RCC) and evaluated the effects of the targeted therapies treated with sorafenib and sunitinib.

Expression of HO-1 in cancer tissue from 66 patients was measured by immunohis-tochemical staining. The patients received either oral sorafenib (n=40) or oral sunitinib (n=26) within 4 weeks after nephrectomy and were followed up long term to determine the tumor response and prognosis.

Our current study revealed a high HO-1 expression level in 57.6% (38/66) of patients and a low HO-1 expression level in 42.4% (28/66) of patients with CC-RCC. The study also revealed that patients with high HO-1 expression did not have a higher objective response rate (2.6% versus 53.6%, P<0.01), clinical benefit rate (47.4% versus 92.9%, P<0.01), longer progression-free survival (4.4 versus 42 months, P=0.022), or overall survival (χ²=4.775, P=0.029) than patients with low HO-1 expression. In the low HO-1 level group, a higher tumor response rate and a longer survival time was achieved in patients who received sorafenib or sunitinib. Multivariate analysis showed that HO-1 expression was an independent prognostic factor for tumor response and overall survival.

High expression of HO-1 was associated with a lower tumor response rate and a shorter overall survival time when compared with low expression of HO-1. Overall, HO-1 expression might be a useful biomarker for predicting the response to sunitinib and sorafenib for patients with metastatic CC-RCC.

• HO-1
• renal cell carcinoma
• sorafenib target therapy
• sunitinib

• PD-L1
• Ras protein
• apoptosis
• c-Met
• cancer
• heme oxygenase
• hepatocyte growth factor/scatter factor (HGF/SF)
• renal cancer
• signal transduction

Nrf2 has gained great attention with respect to its pivotal role in cell and tissue protection. Primarily defending cells against metabolic, xenobiotic and oxidative stress, Nrf2 is essential for maintaining tissue integrity. Owing to these functions, Nrf2 is regarded as a promising drug target in the chemoprevention of diseases, including cancer. However, much evidence has accumulated that the beneficial role of Nrf2 in cancer prevention essentially depends on the tight control of its activity. In fact, the deregulation of Nrf2 is a critical determinant in oncogenesis and found in many types of cancer. Therefore, amplified Nrf2 activity has profound effects on the phenotype of tumor cells, including radio/chemoresistance, apoptosis protection, invasiveness, antisenescence, autophagy deficiency, and angiogenicity. The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways. Additionally, alterations of the cellular environment, eg, during inflammation, contribute to Nrf2 deregulation and its persistent activation. Therefore, the status of Nrf2 as anti- or protumorigenic is defined by many different modalities. A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other. The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

• cancer therapy
• carcinogen
• transcription factor
• tumorigenesis
• xenobiotic and oxidative stress

AIM: To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved.

METHODS: Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by a flow cytometric assay. Western blotting was used to measure protein expression. Heme oxygenase (HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes. Reactive oxygen species (ROS) production was monitored by flow cytometry. Caspase-3 activity was measured with a colorimetric assay kit. Mice were inoculated with 1 × 10⁷ tumor cells subcutaneously into the right flanks. All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured.

RESULTS: Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cis-diaminedichloroplatinum (cisplatin; CDDP) compared to other cell lines in vitro. Inhibition of HO-1 expression or activity by zinc protoporphyrin IX (ZnPP IX) markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo. In contrast, induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo. Furthermore, cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity, which paralleled the incidence of cell apoptosis, whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP.

CONCLUSION: ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS.

• Zinc protoporphyrin IX
• Heme oxygenase-1
• Liver cancer cell lines
• Cisplatin
• Chemotherapy

• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Caspase 3/metabolism
• Cisplatin/administration & dosage
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Heme Oxygenase-1/metabolism
• Hemin/pharmacology
• Hep G2 Cells
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mice, Nude
• Oxidative Stress/drug effects
• Protoporphyrins/administration & dosage
• Reactive Oxygen Species/metabolism
• Time Factors
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays

Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the formation of S-adenosylmethionine (SAMe) by joining methionine and ATP. SAMe is a methyl donor for transmethylation and has an important role for DNA and/or protein methylation. MAT2A is expressed widely in many tissues especially in kidney. Several studies have demonstrated that there are abnormal expressions of MAT2A in several kinds of cancers such as liver and colon cancers. But the relationship of MAT2A between renal cell carcinomas (RCC) is less understood.

The mRNA expression level of the MAT2A gene was determined in 24 RCC patients and 4 RCC cell lines, using real-time quantitative-polymerase chain reaction (RT-PCR). The MAT2A protein content was measured by western blotting and immunohistochemical analysis in 55 RCC patients. The mRNA levels of heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were also analysized in patients using RT-PCR. The correlations between the MAT2A and HO-1 as well as COX-2 were analyzed with nonparametric Spearman method.

MAT2A transcript was significantly downregulated in cancer tissues compared to normal tissues (P < 0.05). Immunohistochemical analysis and western blotting indicated that level of MAT2A protein was decreased in cancer tissues. The statistical analysis reveals a negative correlation between MAT2A and HO-1 expression in RCC patients and cell lines (P < 0.01).

This study demonstrated that MAT2A was lower expression in cancer tissues, suggesting that it may be involved in the development of RCC. MAT2A is a transcriptional corepressor for HO-1 expression by supplying SAM for methyltransferases, which may be one of potential mechanism of MAT2A as tumor suppressor in kidney carcinogenesis.

• Adaptive survival response
• Antioxidant response elements
• Chemoresistance
• Free radicals
• Heme oxygenase-1
• Nrf2
• Radioresistance
• Redox balance

• Antineoplastic Agents/therapeutic use
• Gamma Rays/therapeutic use
• Gene Expression Regulation, Neoplastic
• Heme Oxygenase-1/antagonists & inhibitors
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Humans
• Molecular Targeted Therapy
• NF-E2-Related Factor 2/antagonists & inhibitors
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Neoplasms/blood supply
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/therapy
• Neovascularization, Pathologic
• Oxidative Stress
• Photochemotherapy
• Radiation-Sensitizing Agents/therapeutic use
• Signal Transduction
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/radiation effects

Renal interstitial fibrosis is a common final pathological process in the progression of kidney disease. This is primarily due to oxidative stress, which contributes to renal inflammation and fibrosis. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is known to coordinate induction of genes that encode antioxidant enzymes. We investigated the effects of oleanolic acid, a known Nrf2 activator, on oxidative stress-induced renal inflammation and fibrosis.

One day before unilateral ureteral obstruction (UUO) performed in C57BL/6 mice, oleanolic acid treatment was initiated and was continued until 3 and 7 days after UUO. Renal inflammation and fibrosis, markers of oxidative stress, and changes in Nrf2 expression were subsequently evaluated.

In the obstructed kidneys of UUO mice, oleanolic acid significantly attenuated UUO-induced collagen deposition and fibrosis on day 7. Additionally, significantly less inflammatory cell infiltration, a lower ratio of Bax to Bcl-2 expression, and fewer apoptotic cells on TUNEL staining were observed in the obstructed kidneys of oleanolic acid-treated mice. Oleanolic acid increased the expression of nuclear Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and heat shock protein 70, and decreased lipid peroxidation in the obstructed kidney of UUO mice. There were no changes in the expression of total Nrf2 and Kelch-like ECH-associated protein 1, indicating that oleanolic acid enhanced nuclear translocation of Nrf2.

These results suggest that oleanolic acid may exert beneficial effects on renal fibrosis by increasing nuclear translocation of Nrf2 and subsequently reducing renal oxidative stress.

• Apoptosis
• Chemokines
• Heme Oxygenase
• Nrf2
• Nuclear Transport
• Signal Transduction
• Signaling

• HO-1
• Honokiol
• Ras
• Renal tumor
• VEGF

• Apoptosis/drug effects
• Biphenyl Compounds/pharmacology
• Calcineurin/genetics
• Calcineurin/metabolism
• Calcineurin Inhibitors
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cyclosporine/antagonists & inhibitors
• Cyclosporine/pharmacology
• Down-Regulation/drug effects
• Gene Expression Regulation/drug effects
• Genes, ras
• Heme Oxygenase-1/biosynthesis
• Humans
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/genetics
• Kidney Neoplasms/metabolism
• Kidney Neoplasms/pathology
• Lignans/pharmacology
• Phosphorylation/drug effects
• Proto-Oncogene Mas
• Signal Transduction/drug effects
• Transcriptional Activation/drug effects
• Transfection
• Vascular Endothelial Growth Factor A/biosynthesis
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism
• raf Kinases/genetics
• raf Kinases/metabolism
• ras Proteins/genetics
• ras Proteins/metabolism

• R01 AR047901 NIAMS NIH HHS
• R01 CA131145 NCI NIH HHS

• AMP-activated protein kinase
• AMPK
• ARE
• ERK
• HO-1
• Keap1
• Kelch-like ECH-associated protein 1
• Metformin
• Nrf2
• antioxidant response element
• extracellular signal-regulated kinase
• heme oxygenase-1
• nuclear erythroid factor 2 (NE-F2)-related factor 2

• iron (ferric ammonium citrate)
• lysosomes
• ras
• ovarian cancer
• map kinase

• Apoptosis Regulatory Proteins/metabolism
• Autophagy/drug effects
• Autophagy-Related Protein 5
• Autophagy-Related Protein 7
• Beclin-1
• Butadienes/pharmacology
• Cell Line, Tumor
• Cell Survival/drug effects
• Class III Phosphatidylinositol 3-Kinases/metabolism
• Female
• Ferric Compounds/pharmacology
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Humans
• Lysosomes/metabolism
• Membrane Proteins/metabolism
• Microtubule-Associated Proteins/metabolism
• Mitogen-Activated Protein Kinases/antagonists & inhibitors
• Mitogen-Activated Protein Kinases/metabolism
• Nitriles/pharmacology
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Quaternary Ammonium Compounds/pharmacology
• Ubiquitin-Activating Enzymes/metabolism
• ras Proteins/metabolism

• R01 CA123219 NCI NIH HHS
• U54 CA163068 NCI NIH HHS
• R01 CA 123219 NCI NIH HHS

• Apoptosis/physiology
• Blotting, Western
• Carcinoma, Squamous Cell/metabolism
• Cell Proliferation/drug effects
• DEAD Box Protein 58
• DEAD-box RNA Helicases/metabolism
• DEAD-box RNA Helicases/pharmacology
• Dose-Response Relationship, Drug
• Head and Neck Neoplasms/metabolism
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Interferon-Induced Helicase, IFIH1
• RNA, Small Interfering/genetics
• Receptors, Immunologic
• Transfection

H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology. H-RasV12 expressing cells also show premature senescence followed by cell death, induced by autophagy and apoptosis. In this context, we provide evidence that in H-RasV12 expressing cells, the premature senescence is associated with cellular redox imbalance as well as with altered post-translation protein modification. In particular, redox imbalance is due to a strong reduction of total antioxidant capacity, and significant decrease of glutathione level. As the reversible addition of glutathione to cysteinyl residues of proteins is an important post-translational regulative modification, we investigated S-glutathionylation in cells expressing active H-Ras. In this contest we observed different S-glutathionylation patterns in control and H-RasV12 expressing cells. Particularly, the GAPDH enzyme showed S-glutathionylation increase and significant enzyme activity depletion in H-Ras V12 cells. In conclusion, we proposed that antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation.

• Antioxidants/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Apoptosis/physiology
• Autophagy/drug effects
• Autophagy/genetics
• Autophagy/physiology
• Cell Cycle/drug effects
• Cell Cycle/genetics
• Cell Cycle/physiology
• Cell Death/drug effects
• Cell Death/genetics
• Cell Death/physiology
• Cell Line
• Cellular Senescence/drug effects
• Cellular Senescence/genetics
• Cellular Senescence/physiology
• Electrophoresis, Gel, Two-Dimensional
• Genes, ras/genetics
• Genes, ras/physiology
• Humans
• Immunoblotting
• Mass Spectrometry
• Oxidation-Reduction
• Reactive Oxygen Species/metabolism

• Animals
• Cell Nucleus/metabolism
• Cells, Cultured
• Culture Media
• Gene Expression
• Glutathione Transferase/analysis
• Glutathione Transferase/genetics
• Hepatocytes/metabolism
• Male
• Methionine/administration & dosage
• Mitogen-Activated Protein Kinase 1/metabolism
• NF-E2-Related Factor 2/physiology
• RNA, Messenger/analysis
• Rats
• Rats, Sprague-Dawley
• Up-Regulation