A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1
A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1
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DOI：
10.1038/s41598-019-51144-6
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发表时间：
2019-10-10
影响因子：
4.6
通讯作者：
Hotomi, Muneki
中科院分区：
文献类型：
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作者：
Enomoto, Keisuke;Sato, Fuyuki;Hotomi, Muneki
由于甲状腺间变性癌（ATC）的致命性和快速进展，迫切需要一种新的治疗方法。我们最近报道了ATC高表达MYC蛋白，并通过其选择性抑制剂JQ 1阻断MYC，降低ATC生长并改善临床前模型中的存活率。MYC的重要作用之一是调节L-中性氨基酸转运蛋白1（LAT 1）的表达，抑制LAT 1的表达也可发挥类似的抗肿瘤作用。我们首先确定，虽然人类ATC表达LAT 1蛋白，但在非癌性甲状腺组织中很少或未检测到，进一步支持LAT 1作为良好靶点。然后，我们通过使用基于细胞的体外研究和携带人ATC细胞的体内异种移植模型来评估LAT 1抑制剂JPH 203对ATC的功效。JPH 203通过抑制mTOR信号，显著抑制ATC细胞增殖，并阻断G 0/G1期细胞向S期的细胞周期进程。在异种移植模型中进一步证实了JPH 203通过抑制mTOR信号传导和G 0/G1细胞周期相关蛋白来抑制肿瘤生长和减小肿瘤大小。这些临床前研究结果表明，LAT 1抑制剂是控制ATC的强有力候选药物，目前的治疗选择非常有限。
A novel therapeutic approach is urgently needed for patients with anaplastic thyroid cancer (ATC) due to its fatal and rapid progress. We recently reported that ATC highly expressed MYC protein and blocking of MYC through its selective inhibitor, JQ1, decreased ATC growth and improved survival in preclinical models. One of the important roles of MYC is regulation of L-neutral amino acid transporter 1 (LAT1) protein and inhibition of LAT1 would provide similar anti-tumor effect. We first identified that while the human ATC expresses LAT1 protein, it is little or not detected in non-cancerous thyroidal tissue, further supporting LAT1 as a good target. Then we evaluated the efficacy of JPH203, a LAT1 inhibitor, against ATC by using the in vitro cell-based studies and in vivo xenograft model bearing human ATC cells. JPH203 markedly inhibited proliferation of three ATC cell lines through suppression of mTOR signals and blocked cell cycle progression from the G0/G1 phase to the S phase. The tumor growth inhibition and decrease in size by JPH203 via inhibition of mTOR signaling and G0/G1 cell cycle associated proteins were further confirmed in xenograft models. These preclinical findings suggest that LAT1 inhibitors are strong candidates to control ATC, for which current treatment options are highly limited.