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.

Comprehensive Characterization of LAT1 Cholesterol-Binding Sites

“…In recent years, LAT1 has emerged as a viable drug target for multiple diseases and disorders such as cancer − and autism spectrum disorder (ASD). , Currently, most of the drug discovery efforts targeting LAT1 have focused on inhibitors targeting the substrate-binding site. For example, there are two orthosteric substrate-binding site inhibitors of LAT1 that are currently under clinical investigation for treating patients with advanced biliary tract cancers (JPH-203) and advanced pancreatic cancer (OKY 034) .…”

Extracellular Vesicles Carrying miR-887-3p Promote Breast Cancer Cell Drug Resistance by Targeting BTBD7 and Activating the Notch1/Hes1 Signaling Pathway

“…It was verified that EVs promote angiogenesis, support the growth and expansion of tumors, and transmit anticancer drugs outside the BC cells, leading to drug resistance [ 34 ]. Moreover, tumors grow and evolve through a constant crosstalk with the surrounding microenvironment, and emerging evidence indicates that angiogenesis and immunosuppression frequently occur simultaneously in response to this crosstalk [ 35 ]. Accordingly, strategies combining antiangiogenic therapy and immunotherapy seem to have the potential to tip the balance of the tumor microenvironment and improve treatment response [ 36 ].…”

Contribution of the L-Type Amino Acid Transporter Family in the Diagnosis and Treatment of Prostate Cancer

“…LAT1 (SLC7A5) was discovered in 1998 [ 3 , 9 ]. It combines with 4F2hc (SLC3A2) heavy chain protein to form a transmembrane complex to play its biological role [ 10 ]. LAT1 is mainly responsible for the transport of large neutral amino acids.…”

“…There is no clear research result on the role of LAT1 in T cell differentiation, but previous studies have shown that LAT1 is related to the metabolic process of T lymphocyte differentiation. LAT1 expression is low in intrinsic T cells, whereas T cells at the differentiation stage specifically increase LAT1 expression by T cell receptors (TCR), ensuring sufficient nutrients to react with the antigen [ 10 , 14 ].…”

“…Among amino acid transporters, LAT1 is selectively hyperactive in a variety of cancer cells [ 10 ]. The pathway for enhancing LAT1-mRNA expression is not yet clear but includes carcinogenic Myc and hyposia-inducedfactors (HIFs) that can enhance its expression.…”