Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.

ABSTRACT: Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. The

SUBMITTER: Xu Q 

PROVIDER: S-EPMC9139506 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature