c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells

Abstract

Abstract. Tumor cells take up a massive amount of nutrition compared to normal cells for increased metabolism. Therefore, special transporters for organic materials are required to satisfy the powerful consumption of nutrition in tumor cells. L-type amino acid transporter 1 (LAT1) incorporates large neutral amino acids, most of which are also categorized as essential amino acids, into cells in a Na + -independent manner. Because of its high expression levels in a variety of cancer cells, it is speculated that LAT1 functions as a key transporter for highly effective delivery of essential amino acids into cancer cells. In this regard, LAT1 inhibitor is expected to have clinical benefit for cancer therapy. However, the molecular mechanism of enrichment of LAT1 in cancer cells remains poorly understood. Here, we show that a proto-oncogene, c-Myc, is a critical positive regulator of LAT1 expression in MIA Paca-2 human pancreatic cancer cells. The uptake of leucine, a representative neutral amino acid, was strictly dependent on LAT1 in MIA Paca-2 cells, and siRNA-mediated knockdown of LAT1 inhibited cell proliferation. Diminished c-Myc expression with siRNA resulted in severe reduction of LAT1 protein levels as well as mRNA levels, which, in turn, led to a significant defect of leucine incorporation. The LAT1 promoter has a canonical c-Myc binding sequence and overexpression of c-Myc increased LAT1 promoter activity, whereas mutation of c-Myc binding site diminished this effect. Our results suggest biological significance of LAT1 in tumor growth and molecular machinery that could explain why LAT1 is preferentially expressed in cancer cells.

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

“…Of note, we assume that the mechanism by which LAT1 expression is induced in T cells is different from the mechanism in cancer cells. Our previous study showed that enrichment of LAT1 expression in cancer cells is mediated by the proto-oncogene c-Myc (37). However, in the same cancer cell lines, we could not detect any effect of either an NF-kB or AP-1 inhibitor on LAT1 expression (K. Hayashi and N. Anzai, unpublished observations).…”

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

“…The frequency of LAT1 expression in the plasma membrane is associated with tumor histology, differentiation grade, pathologic stage, T classification, pleural invasion, lymph-vessel invasion and overall survival rate [27]. LAT1 is also reported as an independent significant prognostic factor in HCC [3] and gastrointestinal cancer such as gastric cancer [28], pancreatic cancer [4,21,29,30], biliary tract cancer [5] and colorectal cancer [31,32]. In pancreatic cancer [4] and biliary tract cancer [5], LAT1 overexpression was significantly associated with cancer stages with lymphatic metastasis and tumor size and strongly correlated with 4F2hc expression in patients with pancreatic cancer [4] and in DLD-1 colorectal cancer cells [31].…”

“…Additionally, Table 1 summarizes LAT1 expression in various types of cancer cell lines and tissues from cancer patients [e.g., non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), gastrointestinal cancer (pancreas, liver, biliary system, colon and rectum), gynecologic cancer (breast, ovary, uterus and cervix), renal cancer, glioma and prostate cancer with an alteration of other associated factors [e.g., 4F2hc, neutral amino acid transporter 2, vascular endothelial growth factor (VEGF), Ki-67, phosphorylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), c-Myc and p53] [4,[18][19][20][21]. The high levels of LAT1 expression are associated with clinicopathological variables used to assess the survival rate of cancer patients such as cancer staging, lymph-node metastasis and lymphatic permeation.…”

Non-essential amino acids attenuate apoptosis of gastric cancer cells induced by glucose starvation

“…The amino acid transporter gene LAT1 has been reported to be upregulated in the membranes of many cancer cells (27,28,(46)(47)(48). This protein transports amino acids into cells and is different from two other amino acid transporter genes, namely LAT2 and h4F2hc (49).…”