Effects of the quercetin derivative CHNQ, a potent aldo- keto reductase inhibitor, on akr1b1 silenced HCT-116 colorectal cancer cells

Download

index.pdf

Date

2016

Author

Taşkoparan, Betül

Metadata

Show full item record

Item Usage Stats

359
views

108
downloads

Aldo-keto reductases (AKRs) are NAD(P)H dependent oxidoreductases that are known to be involved in the biosynthesis, metabolism and detoxification of a number of substrates including glucose. These enzymes are therefore implicated in the development of diabetic complications. Additionally, this family of enzymes, particularly AKR1B1, has been shown to be involved in pathology of inflammation- associated diseases such as atherosclerosis, asthma, uveitis, sepsis, arthritis, periodontitis and cancer, including colorectal cancer (CRC). To better understand the role of AKR1B1 in CRC, we selected the cell line HCT-116 that robustly expresses AKR1B1. Next, we either pharmaceutically inhibited AKR1B1 using 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]- 5-hydroxychromen-4-one (CHNQ), a novel quercetin derivative and AKR1B1 inhibitor, or stably silenced the gene using shRNA. Contrary to our expectations, the cellular effects of CHNQ appeared to be unrelated to its inhibitory effects on AKR1B1; rather it had a significant pro-oxidant effect both in vitro and in vivo by virtue of its 1,4 napthoquinone moiety. Confirming this, we observed an upregulation of the ERK pathway, cell cycle arrest at G2/M phase, induction of apoptosis and decreased cell migration in HCT-116 cells. These effects were similar both in cells with a stable knockdown of AKR1B1 and control cells. On the other hand, we observed that silencing of AKR1B1 itself in HCT-116 cells resulted in decreased proliferation, delayed cell cycle progression, downregulation of the NF- κB pathway as well as impaired cell motility and migration. Taken together, this study provides new data that AKR1B1 may have oncogenic properties in CRC.

Subject Keywords

Quercetin., Cancer cells., Rectum, Colon (Anatomy)

URI

http://etd.lib.metu.edu.tr/upload/12620206/index.pdf
https://hdl.handle.net/11511/25833

Collections

Graduate School of Natural and Applied Sciences, Thesis

Suggestions

OpenMETU
Core

Investigation of the effect of sodium butyrate on the regulation of cyclooxygenase-2 in colon cancer cell lines Caco-2 and HT-29 Ülgen, Doğukan Hazar; Banerjee, Sreeparna; Department of Biology (2015) Sodium butyrate (NaBt) is a four-carbon short-chain fatty acid histone deacetylase inhibitor (HDACi) that is available in the colon through the commensal microbiota-mediated fermentation of dietary fibers. It is the main source of energy for colonocytes, and is regarded to have tumor suppressive effects, most prominently in colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is a gene important in the inflammatory response due to its ability to convert arachidonic acid to prostaglandins. Overexpression and ov...
Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway Canli, Secil Demirkol; Seza, Esin Gulce; Sheraj, Ilir; Gomceli, Ismail; Turhan, Nesrin; Carberry, Steven; Prehn, Jochen H. M.; GÜRE, ALİ OSMAY; Banerjee, Sreeparna (Oxford University Press (OUP), 2020-09-01) AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1(HIGH)) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our previous in silico finding that AKR1B1(HIGH) ...
EFFECT OF TANNIC ACID ON GLUTATHIONE S-TRANSFERASE AND NAD(P)H: QUINONE OXIDOREDUCTASE 1 ENZYMES IN RABBIT LIVER AND KIDNEY KARAKURT, SERDAR; Adalı, Orhan (2011-01-01) Glutathione S-transferase and NAD(P)H: quinone oxidoreductase 1 enzymes have important roles in detoxification and also activation of a wide variety of chemicals. Moreover, resistance of tumor cells against chemotherapeutic agents has been implicated in GST activities. The aim of this study was to investigate the effect of polyphenolic compound tannic acid on rabbit liver and kidney glutathione S-transferase and NAD(P)H: quinone oxidoreductase 1 enzyme activities. Tannic acid was found to be a potent inhibi...
Effect of quercetin on mRNA and protein expressions of vitamin D metabolizing CYP27B1 and CYP24A1 in human embryonic kidney cell line (HEK-293) Durukan, Özlem; Akkulak, Merve; Özhan, Güneş; Evin, Emre; Adalı, Orhan (Wiley, 2018-07-01) Vitamin D is essential compound for life having role not only in the regulation of calcium metabolism but also in the regulation of cell proliferation, immune responses, cardiovascular homeostasis and nervous system. These wide range of actions occur with the enzymatic conversion of vitamin D to 1a,25-dihydroxyvitamin D by cytochrome P450 enzymes (CYPs). While CYP27B1 provides the synthesis of hormonally active form of Vitamin D, 1,25(OH)2D, CYP24A1 involves in catabolism of vitamin D. Quercetin, as one of ...
The Effect of 15-lipoxygenase-1 (15-LOX-1) on angiogenesis in colorectal and prostate cancer Çolakoğlu, Melis; Banerjee, Sreeparna; Department of Biology (2017) 15-lipoxygenase-1 (15-LOX-1) is one of the lipoxygenases (LOX) that are important for the generation of inflammatory bioactive lipids, which then result in the initiation and resolution of inflammation. The enzyme mainly metabolizes the omega-6 fatty acid, linoleic acid, to 13-(S)-HODE. In colorectal carcinoma, the tumor suppressive role of 15-LOX-1 is highlighted with decreased proliferation, induction of apoptosis, reduced motility and invasion. Oppositely, the expression of 15-LOX-1 was reported to have ...

Citation Formats

B. Taşkoparan, “Effects of the quercetin derivative CHNQ, a potent aldo- keto reductase inhibitor, on akr1b1 silenced HCT-116 colorectal cancer cells,” M.S. - Master of Science, Middle East Technical University, 2016.