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

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2016

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Taşkoparan, Betül

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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)

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

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Graduate School of Natural and Applied Sciences, Thesis

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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.