Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.
Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.
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DOI：
10.3390/cancers14102551
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发表时间：
2022-05-22
期刊：
影响因子：
5.2
通讯作者：
Yu, Lushan
中科院分区：
文献类型：
--
作者：
Xu, Qingwen;Liu, Yuxi;Sun, Wen;Song, Tiantian;Jiang, Xintong;Zeng, Kui;Zeng, Su;Chen, Lu;Yu, Lushan
肾细胞癌(RCC)在低氧微环境下蛋氨酸代谢的变化及其机制目前尚不清楚。本研究表明，蛋氨酸代谢的重新编程和随后的谷胱甘肽(GSH)合成是由氨基酸转运蛋白1(LAT1)介导的。相应地，我们提出了LAT1抑制剂JPH203和奥沙利铂的联合治疗策略，该策略在体内和体外都显示了对肾癌的增强治疗效果。肿瘤的低氧微环境和代谢紊乱损害了化疗药物的疗效，导致耐药和肿瘤转移，这一直是包括肾细胞癌在内的实体瘤治疗的一大挑战。本研究从肾癌细胞蛋氨酸代谢的研究入手，论证了低氧条件下肾癌细胞蛋氨酸蓄积的增加是由L氨基酸转运体1(LAT1)介导的。谷胱甘肽(GSH)作为蛋氨酸代谢产物，会通过化学络合作用减弱奥沙利铂的疗效。通过减少体内和体外GSH的生成，LAT1抑制剂JPH203减少蛋氨酸摄取，显著提高肾癌细胞对奥沙利铂的敏感性。因此，我们提出了一种基于奥沙利铂和LAT1抑制剂联合治疗肾癌的有效而稳定的治疗策略，有望在一定程度上解决肾癌对铂类药物的耐药问题，为开发新的治疗策略和肾癌的治疗提供了有意义的见解
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. 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
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
miR-489-3p 和 miR-630 的上调通过靶向 OCT2 抑制肾细胞癌中奥沙利铂的摄取
影响因子：
14.5
作者：
Chen, Lu;Chen, Le;Yu, Lushan
通讯作者：
Yu, Lushan
影响因子：
3.5
作者：
Miousse IR;Pathak R;Garg S;Skinner CM;Melnyk S;Pavliv O;Hendrickson H;Landes RD;Lumen A;Tackett AJ;Deutz NEP;Hauer-Jensen M;Koturbash I
通讯作者：
Koturbash I
影响因子：
4.1
作者：
Lauinger L;Kaiser P
通讯作者：
Kaiser P
DOI：
10.1186/s13046-020-01762-0
发表时间：
2020-11-30
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Quan L;Ohgaki R;Hara S;Okuda S;Wei L;Okanishi H;Nagamori S;Endou H;Kanai Y
通讯作者：
Kanai Y