Abstract 2683: Inhibition of BCAT1 suppresses the expression of pro-metastatic proteins and reduces cancer metastasis

Abstract Recent evidence suggests that the cytosolic presence of branched chain amino acid aminotransferase (BCAT1) in adult tissues is associated with diverse pathological conditions including cancer and inflammatory diseases such as rheumatoid arthritis; in these diseases, BCAT1 appears to modulate the expression of many key proteins and to be a new druggable target. In cancer, BCAT1 physically associates with CD147 and regulates the levels and the cellular localization of the protein in a number of different cell lines in vitro and in vivo. Silencing of Bcat1 gene downregulates the total expression of CD147 in MDA-MB-435 cells, while inhibition of BCAT1 by sodium 4-methyl-5-oxo-hexanoate (ERG240) leads to suppression of the extracellular CD147 in the same cells. In turn, suppression of extracellular CD147 results in downregulation of CD147-associated proteins such as MCT4, matrix metalloproteinases (MMPs), cyclophilin A, and GAPDH. Furthermore, inhibition of BCAT1 is associated with prevention of cancer cell migration and reduction in secretion of metabolic by-products such as lactate. Surprisingly, treatment of MDA-MB-231 tumor-bearing animals with 2-deoxyglucose (2DG), a well-known inhibitor of glycolysis, leads to a decrease in the levels of c-MYC and BCAT1, an increase in the total expression of CD147, and the increased shedding of the extracellular CD147 into the circulation. This observation suggests that BCAT1-driven regulation of CD147 in cancer cells involves a complex mechanism. Inhibition of tumoral BCAT1 is expected to adversely affect the metastatic potential of various tumors not only through a reduction in cell motility but also through alterations in the tumor microenvironment, driven by inhibition of extracellular CD147. Citation Format: Adonia E. Papathanassiu, Hong A. Vu. Inhibition of BCAT1 suppresses the expression of pro-metastatic proteins and reduces cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2683. doi:10.1158/1538-7445.AM2014-2683