Abstract 4340: The amino acid transporter SLC6A14 is an effective drug target for treatment of pancreatic cancer

Pancreatic cancer is the deadliest of all cancers with worst outcome and poor survival rate. Chemotherapy with gemcitabine works well for early stage cancer, but becomes ineffective for advanced-stage cancer. As such, there is a dire need for new approaches to treat this cancer. The metabolism of tumor cells is very different from that of normal cells. In particular, the differences in amino acid metabolism are gaining increasing attention in cancer biology. Selective amino acid transporters are upregulated in cancer in response to the increased demands for amino acids in tumor cells. Such tumor-selective amino acid transporters are logical druggable targets for cancer therapy. As such, pharmacologic blockade of such upregulated transporters would lead to cell death selectively in tumor cells by depriving the tumor cells of essential nutrients. With this in mind, we analyzed 8 different publically available microarray datasets in Gene Expression Omnibus for the amino acid transporters that are upregulated in pancreatic cancer. This led to the identification of three transporters (SLC1A5, SLC7A5, and SLC6A14) that are overexpressed in tumors compared to normal tissue. Among these, the fold-increase in expression was the highest for SLC6A14 in all datasets (range for fold-increase, 1.3 - 163.3; range for p value, 0.05 - 2x10-14). The fold-increase for the other two transporters is 2 at the maximum. We confirmed these findings using primary pancreatic cancer tissues and cancer cell lines. First, we used paired samples of pancreatic cancer tissues and the corresponding adjacent normal tissues. SLC6A14 mRNA was increased at least by 7-fold in tumor versus normal tissue. The same was true with three additional unpaired cancer and normal pancreatic tissues. We then evaluated the expression of the transporter at mRNA and protein level in a normal pancreatic cell line (HPNE) and five different pancreatic cancer cell lines. The transporter expression was higher in cancer cell lines compared to the normal cell line. This was confirmed by immunofluorescence by comparing the transporter expression between the normal cell line HPNE and the cancer cell line BxPC-3. Blockade of the transporter function in BxPC-3 cells with α-methyltryptophan (-MT) induced amino acid starvation, activated autophagy, altered cell cycle distribution and inhibited mTOR and colony formation. Decreased invasion and migration observed with α-MT in tumor cells was associated with a decrease in stabilization of HIF-1α. Xenograft studies in nude mice showed that administration of α-MT decreased the growth of BxPC-3 and Mia PaCa-2 cells into tumor. To conclude, SLC6A14 is upregulated in pancreatic cancer and blockade of the transporter with α-MT shows differential and selective detrimental effects on pancreatic tumor cells, both in vitro and in vivo. These studies identify SLC6A14 as a novel and effective drug target for pancreatic cancer treatment. Citation Format: Yangzom D. Bhutia, Veena Coothankandaswamy, Sha Cao, Ying Xu, Vadivel Ganapathy. The amino acid transporter SLC6A14 is an effective drug target for treatment of pancreatic cancer. [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 4340. doi:10.1158/1538-7445.AM2014-4340