Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma

Kosuke Higuchi,Tomohiko Ichikawa,Shinichi Sakamoto,Yuzuru Ikehara,Nobushige Takeshita,Yoshie Reien,Tomomi Furihata,Naohiko Anzai,Jun Matsushima,Kentaro Okunushi,Kazuyoshi Nakamura,Maihulan Maimaiti,Yusuke Imamura,Keisuke Ando,Tomokazu Sazuka

doi:10.1038/s41598-019-53397-7

Abstract

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.

Highlights

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids
LAT1-mediated leucine uptake is closely linked to the mammalian target of rapamycin signaling pathway, which plays a key role in cell growth, transcription, and translation[17,18]
The results showed that 90 patients (97.8%) were LAT1 expression-positive in their cancerous areas, and two patients were negative

Summary

Introduction

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. Molecularly targeted drugs and, more recently, immune checkpoint inhibitors have been approved and have contributed to the improvement of prognosis for patients with metastatic RCC5,6. Their therapeutic effects are still limited and their side-effects remain difficult issues that often cause treatment failure or require additional therapeutic management[7]. It has been shown that LAT1 is abundantly expressed in various types of cancer, including non-small cell lung cancer, breast cancer, biliary tract cancer, pancreatic cancer, and prostate cancer, in a cancer-associated manner[10,11,12,13,14,15]. Several studies have shown an association of higher LAT1 expression level with poorer prognosis in various types of cancer[12,13,14,15]

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