Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer.

Abstract

Thyroid cancer is the most common malignant endocrine tumor. Differentiated thyroid cancer (DTC) accounts for 95% of thyroid cancer cases. The primary treatment for intermediate‑ and high‑risk DTC is total thyroidectomy. Postoperatively, serum thyroglobulin (Tg) and anti‑Tg antibody (Tg/Ab) levels are monitored to detect residual, recurrent or metastatic disease. Radioactive iodine (¹³¹I) therapy is administered orally when Tg and Tg/Ab levels exceed standard levels. Recombinant human thyroid‑stimulating hormone (rhTSH) administration methods that do not require thyroid hormone withdrawal treatment and hospitalization have been recommended. However, serum Tg levels, a biomarker of thyroid tissue ablation, are often disturbed by Tg/Ab interference, which is observed in one‑quarter of patients with DTC. The present study aimed to elucidate the molecular mechanisms underlying metabolic changes in patients with DTC treated with ¹³¹I, and to identify Tg/Ab‑independent biomarker candidates using the TPC‑1 cell model. Blood serum samples were collected from patients with DTC before and after administration of ¹³¹I, which was performed following stimulation with rhTSH. Intra‑individual variations in Tg and Tg/Ab levels were observed in the same patients before and after ¹³¹I administration. Serum metabolomic analysis showed elevated levels of branched‑chain amino acid (BCAA), including valine, leucine and isoleucine, in all 3 patients, who exhibited favorable clinical outcomes. Although the number of cases was limited, this may suggest a possible association between BCAA levels and treatment response. Additionally, while overall boronophenylalanine uptake decreased in the total cell population after ionizing radiation exposure, the surviving viable TPC‑1 cells exhibited relatively increased amino acid uptake, assessed using boronophenylalanine as a leucine analog, which corresponded to the findings presented in the cell‑based experiments. Higher expression levels of the CD98 cell surface antigen were observed in irradiated TPC‑1 cells compared with non‑irradiated controls, which may contribute to increased uptake of BCAAs. However, the mRNA expression levels of L‑type amino acid transporter type 1 (LAT1), L‑type amino acid transporter type 2 and CD98hc did not change upon exposure to IR. These results indicated that the increased BCAA uptake in IR‑exposed DTC cells was a transient response likely mediated by LAT1/CD98hc at the cell surface, as suggested by flow cytometry analysis, despite no corresponding increase in LAT1 mRNA expression.