Abstract 450: Aldo-keto reductase family 1 member b1 links glucose metabolism to epithelial-to-mesenchymal transition
Authors: Schwab Annemarie , Siddiqui Aarif , Vazakidou Maria Eleni , Napoli Francesca , Boettcher Martin , Menchicchi Bianca , Rapa Ida , Waldner Maximilian , Mougiakakos Dimitrios , Volante Marco , Greten Florian , Brabletz Thomas , Ceppi Paolo 
Published: July 2017

Introduction: We performed a bioinformatic analysis to identify metabolic genes connected with the process of epithelial-to-mesenchymal-transition (EMT) and the results indicated a possible role for aldo-keto reductase family 1 member B1 (AKR1B1). AKR1B1 is a member of the polyol pathway responsible for catalyzing the reduction of numerous aldehydes, such as glucose. Based on the importance of EMT during carcinogenesis and metastatic progression and on the relevance of enhanced glycolytic rate in cancer cells, we investigated a direct role for AKR1B1 during EMT and tumor progression.

Experimental Procedure: The bioinformatic analysis was performed on datasets from the NCI60 panel of cancer cell lines. Cancer cells from lung, breast and ovarian origin have been investigated in vitro: changes in EMT markers were monitored by western blotting as well as immunofluorescence, growth assays were performed using the IncuCyte® ZOOM, migration rate was tested by wound-healing assays. Changes in stem-like properties were determined by western blotting, FACS and sphere-formation assays. Immunohistochemistry (IHC) was performed on FFPE specimens from lung cancer patients. Additionally, IHC was performed on samples from a mouse model of AOM-induced colon tumorigenesis in mice with an intestinal epithelial cell-specific p53 deletion (which were shown to undergo EMT) and in the wildtype counterparts.

Results: AKR1B1 gene and protein expression was found significantly higher (7-fold) in mesenchymal-like cells. ShRNA-mediated knockdown of AKR1B1 lead to mesenchymal-to-epithelial transition in vitro and suppressed EMT induced by TGF-β or by high glucose levels. Besides reduced migration, AKR1B1-deficient cells displayed decreased proliferation rate and colony-formation ability. Moreover, AKR1B1 knockdown or its inhibition with specific drugs diminished cancer stem cells. The phenotypes observed with AKR1B1 knockdown could be obtained by targeting sorbitol dehydrogenase (SORD), the second and last enzyme of the polyol pathway. Suppression of each enzyme resulted in an impaired glycolytic and oxidative metabolism and adding fructose, the end-product of the polyol pathway, rescued the expression of EMT markers. IHC on samples from the AOM-induced colon cancer model indicated a higher AKR1B1 expression in invasive tumors from p53ΔIEC mice as compared to both p53-deficient non-invasive or wildtype tumors. Finally, AKR1B1 staining of cancer tissues from a cohort of lung cancer patients confirmed a significant correlation with EMT and a negative prognostic value.

Conclusion: In summary, we describe a glucose-related pathway with a previously unknown role in regulating cancer plasticity and EMT, which links altered glucose metabolism to growth and migratory ability, with several potential implications. Targeting polyol pathway enzymes could be a potentially effective therapeutic strategy to arrest cancer progression.

Citation Format: Annemarie Schwab, Aarif Siddiqui, Maria Eleni Vazakidou, Francesca Napoli, Martin Boettcher, Bianca Menchicchi, Ida Rapa, Maximilian Waldner, Dimitrios Mougiakakos, Marco Volante, Florian Greten, Thomas Brabletz, Paolo Ceppi. Aldo-keto reductase family 1 member b1 links glucose metabolism to epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2017-450