Date

2022-2-8

Author

Tuğral, Hoşnaz

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Hepatocellular carcinoma (HCC) is projected to account for 4.7 percent of all new cancer cases and 8.2 percent of all cancer-related deaths globally. NADPH- dependent aldoketoreductases (AKRs) can reduce carbonyl substrates like glucose, sugar aldehydes, keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products. A member of this family of enzymes, AKR1B10, is thought to be a robust early marker for HCC as well as a predictor of poor prognosis. Oxidative stress in cells may result from an imbalance between the synthesis and buildup of reactive oxygen species (ROS). Mitigation of oxidative stress is largely dependent on the activation of enzymes that can reduce ROS using electrons from the cofactor NADPH. NADPH can be consumed by reductive reactions such as fatty acid synthesis, which mainly occurs in the liver. The pentose phosphate pathway (PPP) is one of the primary sources of NADPH in the cell. We have hypothesized that AKR1B10 may have a cross talk with the PPP and alter the antioxidant response or fatty acid metabolism. To address this, I treated HCC cell lines expressing AKR1B10 with the pro-oxidant Manumycin A or with 6-AN, a PPP inhibitor. We observed that HuH-7 cells showed a robust antioxidant response and survival when treated with Manumycin A, whereas SNU-423 cells were highly vulnerable to the vdrug. A higher antioxidant response was observed in stressed SNU423 cells expressing AKR1B10, however, this response was not sufficient to restore survival. Unlike SNU423 cells, Huh-7 cells showed high survival when treated with to 6-AN, indicating that these cells were not reliant on NADPH from the PPP for their survival. 6-AN treatment, however, increased the phosphorylation of ACC as well as AMPK in HuH7 cells, especially in cells that ectopically expressed AKR1B10, suggesting the induction of fatty acid oxidation. The same cells were also highly vulnerable to CoCl 2 indicating high reliance of oxygen for survival. Taken together, our results suggest that AKR1B10 expression in HCC can not only increase an antioxidant response, but also increase fatty acid oxidation for energy generation, providing a mechanistic basis for poor prognosis observed with high expression of AKR1B10 in HCC.

Subject Keywords

aldo-keto reductases, ROS, NADPH, pentose phosphate pathway

URI

https://hdl.handle.net/11511/96387

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Graduate School of Natural and Applied Sciences, Thesis