An investigation of AKR1B1 and AKR1B10 in gastrointestinal cancers

Date

2023-9-07

Author

Seza, Esin Gülce

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Aldo-keto reductases (AKRs) are a large family of oxidoreductases that can utilize electrons from NADPH to reduce many substrates. AKR1B1 and AKR1B10 are among the extensively studied human AKRs due to their roles in the polyol pathway and detoxification reactions, respectively. Our previous research has shown that AKR1B1 and AKR1B10 have diverse effects on colorectal cancer. Using ex vivo samples from colon and rectal tumor patients, I have shown that AKR1B1 expression was associated with a stronger mesenchymal phenotype and worse prognosis, while AKR1B10 expression was associated with the activation of metabolic pathways. Next, using hepatocellular carcinoma (HCC) cell lines with differing metabolic characteristics and low endogenous AKR1B10 expression, I aimed to understand the effect of AKR1B10 on metabolic reprogramming. Forced expression of AKR1B10 in the glycolytic cell line SNU423 activated signaling suggesting enhanced fatty acid synthesis and generation of reactive oxygen species. Overexpression of AKR1B10 in the oxidative cell line HuH-7 resulted in low viability and activation of the nutrient sensor AMPK, especially when glucose and glutamine were withdrawn. Untargeted metabolomics of glucose/glutamine starved AKR1B10 expressing HuH-7 revealed for the first time enhanced gluconeogenesis, most likely for biomass generation and a slower TCA cycle, reflecting poor energetics. Metabolic reprogramming and activation of invasion and metastasis are considered among the major hallmarks of cancer. Overall, my data suggests that AKRs may play critical roles in enhancing both metastatic spread and deregulated metabolism, providing a mechanistic basis for their association with poor prognosis in gastrointestinal cancers.

Subject Keywords

Colorectal cancer, Hepatocellular carcinoma, AKR1B1, AKR1B10

URI

https://hdl.handle.net/11511/105505

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Graduate School of Natural and Applied Sciences, Thesis