Abstract LB-156: The role of AKR1B10 in early tumorigenesis depends on AMP-activated protein Kinase-α checkpoint

Abstract

Abstract The role of AKR1B10 in early tumorigenesis depends on AMP-activated protein Kinase-α checkpoint Jun Ma and Deliang Cao 1Department of Medical Microbiology, Immunology, & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL 62794. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in 71.4% ductal carcinoma in situ (DCIS) and 83.6% invasive breast cancer. Furthermore, AKR1B10 expression is correlated significantly with tumor size, node status and disease-related survival. In malignant cells, AKR1B10 promotes cell growth and survival via provoking cellular lipid synthesis and eliminating cytotoxic α, β-unsaturated carbonyl compounds. Therefore, AKR1B10 may play an oncogenic role in tumor growth and progression. This study is aimed to explore the role of AKR1B10 in early tumorigenesis. Interestingly, our data show that the expression of AKR1B10 in MCF10A cell, a normal breast epithelium cell line, led to elevation of p53 levels and premature senescence. However, in RAO-1 cells, an hTERT-immortalized breast epithelium cell line, AKR1B10 expression promoted glucose uptake, glycolysis and fatty acid synthesis, and subsequent cell growth instead. Further studies revealed that AMP-activated protein kinase-alpha (AMPKα), which is an important metabolic barrier during cell transformation, was activated upon AKR1B10 expression in both cell lines. On the other hand, down-regulation of AMPKα by shRNA rescued AKR1B10-induced senescence in MCF10A while partially abrogated pro-metabolism effect of AKR1B10 in RAO-1 cells and caused cell growth inhibition. In summary, the role of AKR1B10 in early tumorigenesis depended on AMPKα checkpoint. When this checkpoint is intact, AKR1B10 activates AMPKα and triggers p53 activation and consequential cellular senescence. On the contrary, when this checkpoint is dysfunctional, such as in cells with constitutive expression of telomerase, AKR1B10 activates AMPKα, enhances glucose and lipid metabolism and promotes cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-156. doi:1538-7445.AM2012-LB-156