Browsing by Author "Sniegowski, Tyler (TTUHSC)"
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Item Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer(2023) Sniegowski, Tyler (TTUHSC); Rajasekaran, Devaraja (TTUHSC); Sennoune, Souad R. (TTUHSC); Sunitha, Sukumaran (TTU); Chen, Fang (TTU); Fokar, Mohamed (TTU); Kshirsagar, Sudhir (TTUHSC); Reddy, P. Hemachandra (TTUHSC); Korac, Ksenija (TTUHSC); Mahmud Syed, Mosharaf (TTUHSC); Sharker, Tanima (TTUHSC); Ganapathy, Vadivel (TTUHSC); Bhutia, Yangzom D. (TTUHSC)Pancreatic ductal adenocarcinoma (PDAC) cells have a great demand for nutrients in the form of sugars, amino acids, and lipids. Particularly, amino acids are critical for cancer growth and, as intermediates, connect glucose, lipid and nucleotide metabolism. PDAC cells meet these requirements by upregulating selective amino acid transporters. Here we show that SLC38A5 (SN2/SNAT5), a neutral amino acid transporter is highly upregulated and functional in PDAC cells. Using CRISPR/Cas9-mediated knockout of SLC38A5, we show its tumor promoting role in an in vitro cell line model as well as in a subcutaneous xenograft mouse model. Using metabolomics and RNA sequencing, we show significant reduction in many amino acid substrates of SLC38A5 as well as OXPHOS inactivation in response to SLC38A5 deletion. Experimental validation demonstrates inhibition of mTORC1, glycolysis and mitochondrial respiration in KO cells, suggesting a serious metabolic crisis associated with SLC38A5 deletion. Since many SLC38A5 substrates are activators of mTORC1 as well as TCA cycle intermediates/precursors, we speculate amino acid insufficiency as a possible link between SLC38A5 deletion and inactivation of mTORC1, glycolysis and mitochondrial respiration, and the underlying mechanism for PDAC attenuation. Overall, we show that SLC38A5 promotes PDAC, thereby identifying a novel, hitherto unknown, therapeutic target for PDAC.Item Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth(2022) Korac, Ksenija (TTUHSC); Rajasekaran, Devaraja (TTUHSC); Sniegowski, Tyler (TTUHSC); Schniers, Bradley K. (TTUHSC); Ibrahim, Andrew F. (TTU); Bhutia, Yangzom D. (TTUHSC)IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.