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

SIMPLE SUMMARY: The transformation and mechanism of methionine metabolism of renal cell carcinoma (RCC) under a hypoxic microenvironment is not well understood as yet. This study illustrated that the reprogramming of methionine metabolism and the subsequent glutathione (GSH) synthesis were mediated by amino acid transporter 1 (LAT1). Correspondingly, we proposed a combination strategy of LAT1 inhibitor JPH203 and oxaliplatin, which presented an enhanced therapeutic efficacy for RCC both in vivo and in vitro. 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. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment