Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

Abstract

Tumor cells are known for their ability to proliferate. Nutrients are essential for rapidly growing tumor cells. In particular, essential amino acids are essential for tumor cell growth. Tumor cell growth nutrition requires the regulation of membrane transport proteins. Nutritional processes require amino acid uptake across the cell membrane. Leucine, one of the essential amino acids, has recently been found to be closely associated with cancer, which activate mTOR signaling pathway. The transport of leucine into cells requires an L-type amino acid transporter protein 1, LAT1 (SLC7A5), which requires the 4F2 cell surface antigen heavy chain (4F2hc, SLC3A2) to form a heterodimeric amino acid transporter protein complex. Recent evidence identified 4F2hc as a specific downstream target of the androgen receptor splice variant 7 (AR-V7). We stressed the importance of the LAT1-4F2hc complex as a diagnostic and therapeutic target in urological cancers in this review, which covered the recent achievements in research on the involvement of the LAT1-4F2hc complex in urinary system tumors. In addition, JPH203, which is a selective LAT1 inhibitor, has shown excellent inhibitory effects on the proliferation in a variety of tumor cells. The current phase I clinical trials of JPH203 in patients with biliary tract cancer have also achieved good results, which is the future research direction for LAT1 targeted therapy drugs.

Keywords: 4F2 cell-surface antigen heavy chain (4F2hc, SLC3A2); L-type amino acid transporter 1 (LAT1, SLC7A); diagnosis; targeted therapy; urinary system tumors.

Figure 1

Structure of LAT1-4F2hc Complex: (A) Hypothetical model of the complex of LAT1 and 4F2hc; (B) LAT1 has 12 transmembrane units, while 4F2hc has only one. The two are covalently connected by disulfide bonds; (C) FIG1 (C) Images created using Mol*, the PDB ID: 6IRS, Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. [19], Mol* (D. Sehnal, S. Bittrich, M. Deshpande, R. Svobodová, K. Berka, V. Bazgier, S. Velankar, S.K. Burley, J. Koča, A.S. Rose (2021) Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Research. doi: 10.1093/nar/gkab314 [21]), and RCSB PDB.

Figure 2

The Major Signaling Pathways Affected by LAT1-4F2hc Complex: The LAT1-4F2HC complex not only enhances mTORC1 activity but also enhances MYC and EZH2 signaling pathways. Moreover, it can affect the proliferation of cancer cells through AKT, MAPK and cell cycle-related P21 and P27 signaling pathways.

Figure 3

LAT Expression is Coordinately Regulated During Prostate Cancer Progression: Proposed model of LAT1-4F2hc/LAT3 in HSPC to CRPC. As HSPC progresses to CRPC, AR acts in reverse to cause low expression of LAT3 and high expression of LAT1.

Figure 4

Relationship of LAT1-4F2hc and PCa & CRPC: The relationship between LATx-4F2hc and AR(AR-V7) and different stages of prostate cancer. Reduced androgen receptor signaling and variation of androgen receptors may result in decreased LAT3 expression and higher LAT1 expression.