Melatonin Inhibits Metastasis of Sunitinib-Resistant Renal Cell Carcinoma Cells Via the GRP78/p38/CTSD Expression

IF 7.5 1区医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Pineal Research Pub Date : 2026-09-10 DOI:10.1111/jpi.70183

Po-Yu Huang, Yi-Hsien Hsieh, Yong-Syuan Chen, Tung-Wei Hung, Hui-Ling Chiou, Pei-Ni Chen, Chun-Wen Cheng, Jen-Pi Tsai

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Abstract

Sunitinib resistance contributes to poor outcomes in advanced renal cell carcinoma (RCC). This study investigated the anti-metastatic effects and underlying mechanisms of melatonin in sunitinib-resistant (SR)-RCC. Melatonin significantly inhibited the migration and invasion of A498-SR and Caki-1-SR cells. SR-RCC cells exhibited elevated CTSD expression, impaired endoplasmic reticulum (ER) stress signaling with reduced GRP78 and IRE1α, and enhanced p38 MAPK activation, all of which were reversed by melatonin. Silencing p38 MAPK further potentiated the inhibitory effects of melatonin on cell migration and invasion. Mechanistically, CTSD expression was regulated through both GRP78/p38 MAPK-mediated ER stress. In vivo, melatonin markedly reduced lung metastasis of Caki-1-SR cells without causing significant toxicity to major organs. Collectively, these findings demonstrate that melatonin inhibited the metastatic potential of SR-RCC by decreasing CTSD expression, restoring ER stress response, and decreasing p38 MAPK expression, supporting its potential as an anti-metastatic therapeutic agent for SR-RCC

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褪黑素通过GRP78/p38/CTSD表达抑制舒尼替尼耐药肾癌细胞转移

舒尼替尼耐药导致晚期肾细胞癌（RCC）预后不良。本研究探讨褪黑素在舒尼替尼耐药(SR)-RCC中的抗转移作用及其潜在机制。褪黑素显著抑制A498-SR和Caki-1-SR细胞的迁移和侵袭。SR-RCC细胞表现出CTSD表达升高，内质网（ER）应激信号受损，GRP78和IRE1α降低，p38 MAPK激活增强，所有这些都可以通过褪黑激素逆转。p38 MAPK的沉默进一步增强了褪黑素对细胞迁移和侵袭的抑制作用。机制上，CTSD的表达通过GRP78/p38 mapk介导的内质网应激来调节。在体内，褪黑素可以显著减少Caki-1-SR细胞的肺转移，而不会对主要器官造成明显的毒性。总之，这些发现表明褪黑素通过降低CTSD表达、恢复内质网应激反应和降低p38 MAPK表达来抑制SR-RCC的转移潜力，支持其作为SR-RCC抗转移治疗药物的潜力。

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来源期刊

Journal of Pineal Research 医学-内分泌学与代谢

CiteScore

17.70

自引率

4.90%

发文量

审稿时长

1 months

期刊介绍： The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.