Abstract 2018: Understanding the functional significance of Sulfiredoxin in cancer cell metabolism
Authors: Jiang Hong , Hao Yanning , Ding Na , Thapa Pratik , Alshahrani Aziza , Lane Andrew N. , Wei Qiou 
Published: July 2021

Intracellular antioxidant enzymes are critical for the maintenance of redox homeostasis under both physiological and pathological conditions, and their expression levels are frequently upregulated in different types of human cancer. Compared to normal cells, cancer cells accommodate energy needs preferentially through aerobic glycolysis that predisposes advantages in cell growth, proliferation, survival, and chemotherapeutic resistance. Whether and how redox enzymes contribute to cancer cell metabolism has not been fully explored. Sulfiredoxin (Srx) is a unique reducing enzyme that can restore the peroxidase activity of hyperoxidized peroxiredoxins. It also promotes oncogenic signaling to facilitate tumor growth and malignant progression in multiple types of human cancer including non-small cell lung cancer. To investigate the significance and molecular mechanism of Srx in cancer cell metabolism, endogenously expressed Srx in human non-small cell lung cancer cells was depleted by lentivirus mediated ShRNA knockdown technique. Features of cellular metabolism, including the uptake/consumption of glucose, the production of lactate, the rate of extracellular acidification and the generation of energy were measured using series of quantitative assays and the seahorse real-time cell metabolic analysis. In particular, the fate and routes of glucose metabolism in groups of control and Srx-depleted cells were determined and compared with the addition of C13-glucose into the culture medium, and metabolites were qualitatively and quantitatively measured using stable isotope-resolved metabolomic method. To determine the molecular mechanism of metabolic change, genes differentially expressed in control and Srx knockdown cells were identified by DNA microarray. Genes with statistically significant changes on expression levels were further validated by quantitative real-time PCR at the transcript level and immunoblotting at the protein level. We demonstrated that knockdown of Srx in human lung cancer cells leads to a significant change of glucose metabolism, characterized by the metabolic reprogramming from predominantly glycolysis to oxidative phosphorylation. This transition is likely resulted from a profound change of gene expression pattern due to the knockdown of Srx. For example, among those downregulated genes there are transporters for glucose and monocarboxylate. In summary, our data indicate that depletion of Srx in lung cancer cells leads to metabolic reprogramming that favors oxidative phosphorylation, and further investigation of this process may be valuable for the complete understanding of the functional significance of redox enzymes in the development of not only lung but also other types of human cancer.

Citation Format: Hong Jiang, Yanning Hao, Na Ding, Pratik Thapa, Aziza Alshahrani, Andrew N. Lane, Qiou Wei. Understanding the functional significance of Sulfiredoxin in cancer cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2018.