L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism

Abstract

Abstract18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.

LAT1 inhibitor JPH203 sensitizes cancer cells to radiation by enhancing radiation-induced cellular senescence

“…Sato et al . reported that LAT1 knockout decreased cellular ATP levels, and LAT1 overexpression increased it [36] . To examine the effect of JPH203 on ATP synthesis after irradiation, we measured the cellular ATP content after irradiation with or without JPH203 ( Fig.…”

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

“…ERα enhances the expression of L-type amino acid transporter 1 (LAT1, SLC7A2 [385][386][387], which increases cellular leucine influx activating mTORC1 [73][74][75][76][77][78][79][80][81][82][83][84]. In fact, increased expression of LAT1 has been reported in BC [388,389], preferentially in chemoresistant BC [390]. Of note, proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ BC cells [391].…”

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer

“…Immunohistochemistry was performed as previously reported [5]. We used LAT1 mouse monoclonal antibody (1:100, KE023 Trans Genics, Hyogo, Japan) and LAT3 rabbit polyclonal antibody (1:1000, MBL Life science, Tokyo, Japan).…”

“…Essential amino acids (EAAs) imported by several amino acid transporters have been generally considered pivotal for cell proliferation because the depletion of even a single EAA in vitro induced cell death [4,5]. Among those transporters, the L-type amino acid transporter (LAT1) family is essential for EAAs uptake and comprises four members (LAT1-LAT4); LAT1 has been proposed especially fundamental to cancer viability and reported to be abundant in malignant cells compared to normal cells [6,7].…”