Association of High LAT1 Expression with Poor Prognosis and Recurrence in Colorectal Cancer Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy

Int J Mol Sci. 2023 Jan 30;24(3):2604. doi: 10.3390/ijms24032604.

Abstract

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

Keywords: L-type amino acid transporter-1; cancer aggressiveness; chemosensitivity marker; prognostic marker.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Chemotherapy, Adjuvant
  • Colorectal Neoplasms* / metabolism
  • Fluorouracil / therapeutic use
  • Humans
  • Oxaliplatin / pharmacology
  • Oxaliplatin / therapeutic use
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Fluorouracil
  • Oxaliplatin
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • SLC7A5 protein, human

Grants and funding

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grant numbers 20K16406 and 22H02912). It was also partially supported by a Research Grant of the GIAR Linkage Grant 2022.