Abstract 1798: Glyoxalase 1 (GLO1) as an oncometabolic enabler of prostate cancer progression: CRISPR/Cas9-based GLO1-deletion from human DU145-Luc2 cells blocks EMT and bone metastasis in SCID mice

Abstract

Abstract Glyoxalase 1 (encoded by GLO1) is a glutathione-dependent enzyme detoxifying the glycolytic byproduct methylglyoxal (MG), an oncometabolite involved in metabolic reprogramming. Recently, we have demonstrated that GLO1 is overexpressed in human prostate cancer cells and patient tumors. In order to inform the ongoing debate on the role of GLO1 as an oncometabolic enabler of tumor glucose metabolism and malignant progression, we performed CRISPR/Cas9-based GLO1-deletion in human DU145-Luc2 malignant prostate cancer cells. NanoString nCounterTM ('PanCancer-Progression-Panel') comparative gene expression profiling (GLO1_KO versus GLO1_wt) revealed a significant downregulation of EMT-related pathways in GLO1_KO cells; concordantly, phenotypical screening indicated a pronounced attenuation of matrigel invasiveness observable in GLO1_KO cells. Likewise, inclusion of MG or a small molecule GLO1 inhibitor (TLSC-702) blocked invasiveness of DU145 GLO1_wt cells. Downregulation of EMT-related genes (including MMP3, SPP1, CXCL8) was accompanied by increased expression of TXNIP (thioredoxin-interacting protein), a master regulator of cellular energy metabolism and redox homeostasis. In a bioluminescent SCID mouse bone metastasis model (intracardial injection of DU145-Luc2 GLO1_wt and GLO1_KO cells), GLO1 expression was necessary to cause mandibular bone metastases (as evidenced by the complete absence of bone metastases after GLO1 deletion). Given the availability of drug-like small molecule inhibitors of GLO1 enzymatic activity these data suggest that GLO1 represents a novel molecular target for the pharmacological suppression of prostate cancer bone metastasis. Citation Format: Jana Jandova, Anne E. Cress, Georg T. Wondrak. Glyoxalase 1 (GLO1) as an oncometabolic enabler of prostate cancer progression: CRISPR/Cas9-based GLO1-deletion from human DU145-Luc2 cells blocks EMT and bone metastasis in SCID mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1798.