Deletion of Slc6a14 reduces cancer growth and metastatic spread and improves survival in KPC mouse model of spontaneous pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is lethal. There is a dire need for better therapeutic targets. Cancer cells have increased demand for sugars, amino acids, and lipids and therefore upregulate various nutrient transporters to meet this demand. In PDAC, SLC6A14 (an amino acid transporter) is upregulated, affecting overall patient survival. Previously we have shown using in vitro cell culture models and in vivo xenograft mouse models that pharmacological inhibition of SLC6A14 with a-methyl-L-tryptophan (a-MLT) attenuates PDAC growth. Mechanistically, blockade of SLC6A14-mediated amino acid transport with a-MLT leads to amino acid deprivation, eventually inhibiting mTORC1 signaling pathway, in tumor cells. Here we report on the effect of Slc6a14 deletion on various parameters of PDAC in KPC mice, a model for spontaneous PDAC. Pancreatic tumors in KPC mice show evidence of Slc6a14 upregulation. Deletion of Slc6a14 in this mouse attenuates PDAC growth, decreases metastatic spread of the tumor, reduces ascites fluid accumulation, and improves overall survival. At molecular level, we show lower proliferation index and reduced desmoplastic reaction following Slc6a14 deletion. Furthermore, we find that deletion of Slc6a14 does not lead to compensatory upregulation in any of the other amino transporters. In fact, some of the amino acid transporters are actually downregulated in response to Slc6a14 deletion, most likely related to altered mTORC1 signaling. Taken together, these results underscore the positive role SLC6A14 plays in PDAC growth and metastasis. Therefore, SLC6A14 is a viable drug target for treatment of PDAC and also for any other cancer that overexpresses this transporter.

A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment

“…Furthermore, laminins LAMBC2 and LAMB3 support cancer progression and resistance to gemcitabine -one of the main chemotherapeutics used in PDAC patients [61,62]. In general, the association with poor prognosis of the stroma signature is consistent with the one described in previous studies for each gene: CEACAM5 [63], CEACAM6 [64], FN1 [65], GJB2 [66], GPRC5A [67], LAMB3 [68,69], LAMC2 [68,69], SFN [70], SLC6A14 [71], TSPAN1 [72], VCAN [65]. The meta-analysis from transcriptomic studies allows a be er understanding of the PDAC environment.…”

Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer

“…RNA isolation and real-time RT-qPCR were performed as described previously 46 , 47 . Briefly, RNA was isolated from cells using Trizol method.…”

Exploiting the Achilles’ heel of cancer: disrupting glutamine metabolism for effective cancer treatment

“…For example, it can help tumor cells take up methionine to maintain DNA methylation and mediate the transport of carnitine ( Nakanishi et al, 2001 ; Sniegowski et al, 2021 ). SLC6A14 is overexpressed in colorectal cancer ( Lu et al, 2022 ), ER + breast cancer ( Karunakaran et al, 2011 ), gastric cancer ( Wang and Wang, 2022 ), pancreatic cancer ( Schniers et al, 2022 ), and cervical cancer ( Sikder et al, 2018 ), closely related to lower overall survival. α-Methyltryptophan (α-MT), a pharmacological inhibitor of SLC6A14, can inhibit the proliferation of cancer cells in vitro and tumor growth in vivo ( Karunakaran et al, 2011 ; Coothankandaswamy et al, 2016 ; Lu et al, 2022 ).…”