Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer

V. Coothankandaswamy, S. Cao, Y. Xu, P. D. Prasad, P. K. Singh, C. P. Reynolds, S. Yang, J. Ogura, V. Ganapathy, Y. D. Bhutia

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Abstract

Background and Purpose: Pancreatic cancer is a solid tumour that is often fatal. Hence, there is an urgent need to identify new drug targets for this disease. Highly proliferating cancer cells have an increased demand for nutrients and, therefore, need to up-regulate selective amino acid transporters. Here, we investigated which amino acid transporters are up-regulated in pancreatic cancer and whether any of these transporters has potential as a drug target for this fatal disease. Experimental Approach: The expression of amino acid transporters in pancreatic cancer was analysed using publicly available microarray datasets, and the findings with the transporter SLC6A14 were validated by mRNA and protein analysis. The potential of SLC6A14 as a drug target was evaluated using a pharmacological blocker in vitro and in vivo. Key Results: SLC6A14 was up-regulated several fold in patient-derived xenografts, primary tumour tissues and pancreatic cancer cells lines compared to normal pancreatic tissue or normal pancreatic epithelial cells. The magnitude of the up-regulation of SLC6A14 was the highest among the amino acid transporters examined. A pharmacological blocker of SLC6A14, α-methyltryptophan, induced amino acid starvation in pancreatic cancer cells and reduced the growth and proliferation of these cells, both in vitro and in vivo. Conclusion and Implications: The salient features of this study are that SLC6A14 is markedly up-regulated in pancreatic cancer and that pharmacological blockade of this transporter interferes with amino acid nutrition and reduces growth and proliferation of pancreatic cancer cells. These findings identify SLC6A14 as a novel druggable target for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)3292-3306
Number of pages15
JournalBritish Journal of Pharmacology
Volume173
Issue number23
DOIs
StatePublished - Jan 1 2016

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ASJC Scopus subject areas

  • Pharmacology

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Coothankandaswamy, V., Cao, S., Xu, Y., Prasad, P. D., Singh, P. K., Reynolds, C. P., Yang, S., Ogura, J., Ganapathy, V., & Bhutia, Y. D. (2016). Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. British Journal of Pharmacology, 173(23), 3292-3306. https://doi.org/10.1111/bph.13616