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

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.