转移是癌症患者死亡的主要原因。L型氨基酸转运蛋白1（LAT1，SLC7A5）是一种高度在各种癌症中表达的独立于Na+的中性氨基酸转运蛋白，它支持了癌细胞的生长。尽管高LAT1表达与癌症转移密切相关，但其在此过程中的作用仍不清楚。本研究旨在使用B16-F10黑色素瘤小鼠模型调查LAT1抑制剂对癌症转移的影响。我们的结果表明，高亲和力的LAT1选择性抑制剂nanvuranlat（JPH203）抑制了B16-F10细胞的增殖、迁移和侵袭。同样，LAT1的沉默减少了细胞的增殖、迁移和侵袭。在肺转移模型中，LAT1抑制剂和LAT1沉默减少了B16-F10的肺转移。此外，在原位转移模型中，nanvuranlat和LAT1沉默抑制了肺部、脾脏和淋巴结的转移。我们发现LAT1抑制剂降低了整合素αvβ3在细胞表面的表达。我们的发现揭示了LAT1抑制剂诱导的mTOR信号通路下调将导致整合素αvβ3的表达减少，从而抑制转移。这些结果突显了LAT1在癌症转移中的关键作用，并暗示LAT1抑制可能作为抗转移癌症治疗的潜在靶点。 © 2023 Springer Nature Limited.

Metastasis is the leading cause of mortality in cancer patients. L-type amino acid transporter 1 (LAT1, SLC7A5) is a Na+-independent neutral amino acid transporter highly expressed in various cancers to support their growth. Although high LAT1 expression is closely associated with cancer metastasis, its role in this process remains unclear. This study aimed to investigate the effect of LAT1 inhibition on cancer metastasis using B16-F10 melanoma mouse models. Our results demonstrated that nanvuranlat (JPH203), a high-affinity LAT1-selective inhibitor, suppressed B16-F10 cell proliferation, migration, and invasion. Similarly, LAT1 knockdown reduced cell proliferation, migration, and invasion. LAT1 inhibitors and LAT1 knockdown diminished B16-F10 lung metastasis in a lung metastasis model. Furthermore, nanvuranlat and LAT1 knockdown suppressed lung, spleen, and lymph node metastasis in an orthotopic metastasis model. We discovered that the LAT1 inhibitor reduced the cell surface expression of integrin αvβ3. Our findings revealed that the downregulation of the mTOR signaling pathway, induced by LAT1 inhibitors, decreased the expression of integrin αvβ3, contributing to the suppression of metastasis. These results highlight the critical role of LAT1 in cancer metastasis and suggest that LAT1 inhibition may serve as a potential target for anti-metastasis cancer therapy.© 2023. Springer Nature Limited.