Abstract 3585: Amino acid transporter SLC6A14: A novel drug target for colorectal cancer

Abstract

Abstract SLC6A14 is a Na+/Cl− -dependent amino acid transporter capable of transporting 18 of the 20 proteinogenic amino acids, including arginine, leucine (mTOR activators) and glutamine (necessary for nucleotide biosynthesis). This transporter is expressed at basal levels in normal colon but significantly upregulated in colorectal cancer (CRC). However, the relevance of this upregulation to disease progression remains unknown. We postulated that deletion of SLC6A14 or pharmacological blockade of its function would suppress CRC by depleting amino acids and interfering with mTOR signaling selectively in tumor cells. To test this postulate, we first used Slc6a14-null mice. With two different models of spontaneous CRC (Apcmin/- and DSS/AOM), we found the tumor incidence and tumor growth were much lower in mice with Slc6a14-null background than in mice with Slc6a14. To evaluate the impact of pharmacologic blockade of the transporter on tumor growth we used a syngeneic tumor mouse model with MC-38 cells (a mouse CRC cell line); blockade of Slc6a14 with alpha-methyl tryptophan (α-MT) markedly reduced tumor growth. We then determined the transcriptome profiles of colonic epithelial cells and colonic non-epithelial cells from wild type mice and Slc6a14-null mice by RNAseq. There were hundreds of genes that were either upregulated or downregulated in the null mice. Ingenuity pathway analysis (IPA) of these data revealed predictive activation of canonical AMPK signaling pathway in colonic epithelial of Slc6a14-null mice. AMPK has anticancer activities by modulating multiple pathways including negatively regulating mTOR signaling. Moreover, upstream analysis showed predictive inactivation of two important tumor growth and survival signaling pathways ERK and EGF in the colon of the null mice. Likewise, significant upregulation of APC downregulated 1 (APCDD1) in epithelial cells in null mice implies predictive suppression of canonical Wnt signaling pathway. We also found marked differences in fecal microbiota as a result of Slc6a14 deletion. There was an increase in the relative abundance of beneficial microbiota including those capable of generating short chain fatty acids and lactic acid in null mice. We conclude that deletion of Slc6a14 or its pharmacological blockade protects against CRC by inducing amino acid starvation in tumor cells, thereby causing changes in multiple signaling pathways and in colonic microbiome. These studies identify SLC6A14 as a novel drug target for the treatment of colorectal cancer. Citation Format: Mohd Omar Faruk Sikder, Sathish Sivaprakasam, Vadivel Ganapathy. Amino acid transporter SLC6A14: A novel drug target for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3585.