Date

2021-2-02

Author

Ermiş, Çağdaş

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The Aldo-Keto Reductases (AKR) are nicotinamide adenine dinucleotide (NAD(P)H) dependent oxidoreductases that function in phase 1 metabolismbyreducingaldehydes and ketones into primary and secondary alcohols. Inthis protein superfamily, the expression of AKR1B1 and AKR1B10 enzymes have been linked by us and others to colorectal cancer (CRC). Over-activation of these enzymes in the presence of excess glucose can result in the activation of the polyol pathway, which causes oxidative stress and might contribute to the progression of cancer. Substrates of the AKR enzymes varyfrom sugars to various chemical carcinogens. Many studies suggest that chemotherapy drugs can also be metabolized by these enzymes, leading to drug resistance. On the other hand, a link between these enzymes and a mesenchymal phenotype has also been gaining attention. In this study, we aimed to investigate the effects of overexpression of two AKR enzymes, AKR1B1 and AKR1B10, on CRC cell line SW480, which does not have the endogenous expression of either gene. We observed that AKR1B1 overexpressing cells showed higher motility and weaker cell-cell adhesionbut no significant change in proliferation. These data are consistent with previous findings on a strong and significant positive correlation between the expression of AKR1B1 and several different mesenchymal markers. We also show for the first time that serum-starvedAKR1B1 expressing cells expressed higher protein levels of arate-limitingenzyme of the pentose phosphate pathway, most likely as a means to cope with the increasedoxidative stress in the starved cells. AKR1B10 overexpressing cells were significantly less motile, showed a slower cell cycle progression and a reduced clonogenic potential. Overall, our data corroborateprevious reports on the highly divergent effects of two very closely related enzymes in colorectal cancer.

Subject Keywords

Colorectal Cancer, AKR1B1, AKR1B10, SW480

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https://hdl.handle.net/11511/89795

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Graduate School of Natural and Applied Sciences, Thesis