Uremic toxin lanthionine interferes with VEGFA, intracellular calcium and PI3K/AKT/mTOR signaling pathway in A-498 clear cell renal carcinoma

Abstract Chronic kidney disease (CKD) and cancer are major and increasingly interconnected health burdens. Uremic toxins, which accumulate as kidney function declines, have been implicated in cancer progression, including site-specific renal cell carcinoma (RCC), but the molecular mechanisms underlying these effects remain poorly understood. This study investigated the effect of lanthionine, a sulfur-containing uremic toxin detected in CKD, at clinically relevant concentrations, in A-498 cells as human clear cell renal carcinoma cell line (ccRCC), and HEK293 as non-malignant renal cells. Our results showed that lanthionine acts in a cell-specific manner, promoting cancer cell migration and invasion, with a more pronounced effect in A-498 cells. Lanthionine selectively modulated VEGFA expression and protein levels in A-498 cells, promoting intracellular calcium levels and PI3K/AKT/mTOR signaling pathway. VEGFA increase appeared to be supported by HIFs overexpression. Importantly, VEGFA silencing in A-498 cells decreased intracellular calcium levels and inhibited PI3K/AKT/mTOR signaling pathway, supporting a functional link between VEGFA and these signaling events. These results provide preliminary in vitro evidence that lanthionine may contribute to ccRCC progression by modulating VEGFA-associated calcium signaling and the PI3K/AKT/mTOR pathway, highlighting a potential molecular link between the uremic milieu and renal cancer progression.