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

Abstract

The L-type amino acid transporter (LAT) family contains four members, LAT1~4, which are important amino acid transporters. They mainly transport specific amino acids through cell membranes, provide nutrients to cells, and are involved in a variety of metabolic pathways. They regulate the mTOR signaling pathway which has been found to be strongly linked to cancer in recent years. However, in the field of prostate cancer (PCa), the LAT family is still in the nascent stage of research, and the importance of LATs in the diagnosis and treatment of prostate cancer is still unknown. Therefore, this article aims to report the role of LATs in prostate cancer and their clinical significance and application. LATs promote the progression of prostate cancer by increasing amino acid uptake, activating the mammalian target of rapamycin (mTOR) pathway and downstream signals, mediating castration-resistance, promoting tumor angiogenesis, and enhancing chemotherapy resistance. The importance of LATs as diagnostic and therapeutic targets for prostate cancer was emphasized and the latest research results were introduced. In addition, we introduced selective LAT1 inhibitors, including JPH203 and OKY034, which showed excellent inhibitory effects on the proliferation of various tumor cells. This is the future direction of amino acid transporter targeting therapy drugs.

Keywords: LAT1; LAT3; diagnosis; prostate cancer; treatment.

Figure 1

The substances that each LAT is mainly responsible for transporting are shown in the figure. LATs provide branched-chain amino acids (BCAA), especially leucine, to mammalian target cells of rapamycin complex 1 (mTORC1), and the mTOR pathway is a major control factor in cell proliferation. Leucine is transported into the cell by LATs, binds to the leucine sensor sestrin2, mTORC1 senses amino acid signal, and GATOR2 acts as mTORC1 agonist. Thus, it can promote the function of the mTOR pathway and achieve the purpose of cell proliferation. In addition, LAT1 can use BCAAs as biosynthetic materials for the metabolic reprogramming of cancer cells. BCAT deaminates free BCAAs to form BCKA. It enters the TCA cycle and is used for energy production and fatty acid metabolism to promote cell proliferation.

Figure 2

The three-dimensional conformation of LATs. Both LAT1 and LAT2 consist of 12 transmembrane domains that form pathways for their substrates. They bind to the heavy glycoprotein subunit 4F2hc via disulfide bonds. Unlike LAT1 and LAT2, the biological functions of LAT3 and LAT4 do not require binding to heavy chains and can exist independently. (Images created using PyMol*, colord by chainbows, the PDB ID: 6IRS, 7CMI, the Uniprot ID: O75387, Q8N370, PyMol* (version 2.5 Schrodinger. Warren L. DeLano), and RCSB PDB, and UniProt).

Figure 3

LAT is linked to both hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). In untreated HSPC, 5-alpha reductase converts testosterone to dihydrotestosterone (DHT), which binds to the androgen receptor (AR), enters the nucleus, and stimulates LAT3 transcription, resulting in enhanced LAT3 expression and contributes to the mTOR pathway activation. When hormone therapy is used to treat PCa, testosterone levels fall, resulting in castration, and ARs that no longer bind DHT change, increase, and generate splicing variants. AR-V7, in particular, can enter the nucleus in the absence of testosterone activation, and 4F2hc is present in its downstream signaling. Furthermore, the removal of leucine from the cells results in the lack of eIF2 repression and the admission of ATF4 into the nucleus. It enhances LAT1 expression, and LAT1 and 4F2hc form a dimer, allowing leucine into the cell and promoting tumor cell proliferation [54].

Figure 4

The 2D (A–C) and 3D (a–c) structures of LATs inhibitors. (Aa) BCH is a transportable system L inhibitor. (Bb,Cc) The core structures of T3 and JPH203 both contain an amino acid backbone and a bulky side chain.

Figure 5

The 2D (A,B) and 3D (a,b) structures of LAT1 inhibitor SKN series and LAT3 inhibitor ESK series. (Aa) SKN series and JPH203 have similar molecular structures. (B,b) The ESK series shows a different molecular structure from LAT1 inhibitors such as T3, JPH203, and SKNs. ESK242 can inhibit both LAT1 and LAT3.