Carbonyl Reductase 3 (CBR3) Mediates 9-cis-Retinoic Acid-Induced Cytostatis and is a Potential Prognostic Marker for Oral Malignancy

Ohkura-Hada, Shuri; Kondoh, Nobuo; Hada, Akiyuki; Arai, Masaaki; Yamazaki, Yutaka; Shindoh, Masanobu; Kitagawa, Yoshimasa; Takahashi, Masayuki; Ando, Toshifumi; Sato, Yasunori; Yamamoto, Mikio

doi:10.2174/1874210600802010078

Cited by 4 publications

(6 citation statements)

References 26 publications

(28 reference statements)

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“…Cbr3 (carbonyl reductase 3) catalyzes the reduction of many endogenous and xenobiotic carbonyl compounds, including steroids and prostaglandins, to their corresponding alcohols. Its expression is reduced in oral squamous cell carcinoma cells when compared to premalignant dysplasias and hyperplasias and has been associated with reduced cell growth and motility (43). Histidine decarboxylase (Hdc) is a member of the histidine metabolism pathway and is responsible for the biosynthesis of histamine.…”

Section: Discussionmentioning

confidence: 99%

Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

Meireles

Esteves

Hirata

et al. 2010

Cancer Prevention Research

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Lung cancer is the leading cause of cancer deaths in the United States, surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/d, 5 d/wk for 3, 8, and 20 weeks). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15K cDNA microarray. Cytochrome P450 1b1, a phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17β-estradiol (E 2 ), was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed in control and smoke-exposed lung tissues at 3, 8, and 20 weeks (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure, including estrogen metabolism. In addition, E 2 was detected within murine lung tissue by gas chromatography-coupled mass spectrometry and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of E 2 within lung tissue when combined with the modulation of cytochrome P450 1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer. Cancer Prev Res; 3(6); 707-17. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

Meireles

Esteves

Hirata

et al. 2010

Cancer Prevention Research

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“…Next, the link between CBR3 and apoptosis is supported by study of Ohkura-Hada et al who showed that CBR3 mediates, at least in part, the cytostatic effects of 9-cis-retinoic acid (RA) in oral squamosus cell carcinoma (OSCC) cells [26]. The anticancer activities of RAs are attributable to growth suppression, the induction of apoptosis, and the suppression of cell migration.…”

Section: Association With Cancermentioning

confidence: 97%

“…There are several retinod analogues that are widely used for therapeutic purposes [152]. Ohkura-Hada et al demonstrated that 9-cis-RA induced CBR3 expression in the OSCC cell line, Ca9-22 [26]. Further, the transfection of Ca9-22 cells with the CBR3 expression vector caused reduced cell growth and migration potential, suggesting that CBR3 is a mediator of cytostatic effects by RA.…”

Section: Association With Cancermentioning

confidence: 99%

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Human Carbonyl Reductases

Malátková¹,

Maser²,

Wsól

2010

CDM

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Enzymatic carbonyl reduction means the formation of a hydroxy function out of a ketone or aldehyde moiety and applies for the metabolism of physiological (endogenous) or xenobiotic (exogenous) molecules. As for endogenous substrates, carbonyl reduction is often part of a reversible oxidoreductase process and involves the activation or inactivation of important signal molecules like steroids, prostaglandins, retinoids and biogenic amines. These reactions are carried out by NAD(P)(H)-dependent dehydrogenases belonging to two protein superfamilies, the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). With regard to exogenous substrates, carbonyl reduction of xenobiotics is generally a "one-way" detoxification reaction, since the resulting alcohol is easier to conjugate and to eliminate. Interestingly, the participating enzymes do also belong to the AKR and SDR superfamilies. Moreover, some enzymes from the two protein superfamilies exhibit pluripotency in that they are able to catalyze the oxidoreduction of endobiotics but do also function in the reductive metabolism of carbonyl group bearing xenobiotics. A special case are carbonyl reductases per se which belong to the SDR superfamily and whose substrates or physiological roles are not quite clear. Usually, carbonyl reductases have a broad and diverse substrate spectrum for xenobiotics, however, for some of them a specific physiological function has been speculated. In the human genome, three SDR genes have been identified to code for the carbonyl reductases CBR1 (SDR21C1), CBR3 (SDR21C2) and CBR4 (SDR45C1). The present review summarizes the current knowledge on these enzymes with special emphasis on their role as a defence system against toxicants, as well as their possible physiological function and medical application. In detail, we have screened the recent literature on these three enzymes with regard to endogenous and exogenous substrates, their three-dimensional structure, tissues specific expression, polymorphisms, transcriptional regulation, occurrence in pathological states, and their possible association with cancer. Combined, this review contributes to understanding the complex nature and biological roles(s) of the human carbonyl reductases CBR1, CBR3 and CBR4.

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“…CBR3 is involved not only in the metabolism of anthracyclines, but also in some physiological regulations. Treatment with 9‐ cis ‐retinoic acid induces CBR3 gene expression, and the induced enzyme suppresses cell growth and migration potential in oral squamous cell carcinomas (Ohkura‐Hada et al, ). Furthermore, increased expression of the CBR3 gene in human adipose tissues is negatively associated with fasting insulin and systemic insulin resistance, suggesting that CBR3 modulates the diabetic state (Chang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Identification of a functional antioxidant responsive element in the promoter of the Chinese hamster carbonyl reductase 3 (Chcr3) gene

Miura

Taketomi

Nakabayashi

et al. 2015

Cell Biology International

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CHCR3, a member of the short-chain dehydrogenase/reductase superfamily, is a carbonyl reductase 3 enzyme in Chinese hamsters. Carbonyl reductase 3 in humans has been believed to involve the metabolism and/or pharmacokinetics of anthracycline drugs, and the mechanism underlying the gene regulation has been investigated. In this study, the nucleotide sequence of the Chcr3 promoter was originally determined, and its promoter activity was characterised. The proximal promoter region is TATA-less and GC-rich, similar to the promoter region of human carbonyl reductase 3. Cobalt stimulated the transcriptional activity of the Chcr3 gene. The results of a luciferase gene reporter assay demonstrated that cobalt-induced stimulation required an antioxidant responsive element. Forced expression of Nrf2, the transcription factor that binds to antioxidant responsive elements, enhanced the transcriptional activity of the Chcr3 gene. These results suggest that cobalt induces the expression of the Chcr3 gene via the Nrf2-antioxidant responsive element pathway.

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Carbonyl Reductase 3 (CBR3) Mediates 9-cis-Retinoic Acid-Induced Cytostatis and is a Potential Prognostic Marker for Oral Malignancy

Cited by 4 publications

References 26 publications

Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

Early Changes in Gene Expression Induced by Tobacco Smoke: Evidence for the Importance of Estrogen within Lung Tissue

Human Carbonyl Reductases

Identification of a functional antioxidant responsive element in the promoter of the Chinese hamster carbonyl reductase 3 (Chcr3) gene

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