Zinc as a Dual-Condition Inhibitor of HIF-1α/VEGF-α–Mediated Angiogenesis in Clear Cell Renal Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is marked by aberrant hypoxia-driven signaling and enhanced angiogenesis mediated by hypoxiainducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor alpha (VEGF-α). Zinc (Zn), an essential trace element with emerging anticancer potential, was evaluated for its ability to modulate angiogenesis in von Hippel–Lindau (VHL)-deficient 786-0 cells under normoxic and hypoxic conditions. Using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence, we observed that Zn treatment reduced HIF-1α expression and VEGF-α secretion across both oxygenation states. Notably, Zn inhibited the hypoxia-induced nuclear accumulation of HIF-1α and attenuated paracrine endothelial activation, as shown by reduced human umbilical vein endothelial cell (HUVEC) viability in conditioned media assays. These effects likely involve transcriptional repression, enhanced proteasomal degradation of HIF-1α, and interference with VEGF-α–dependent signaling. Overall, our findings suggest that zinc may function as a multifunctional modulator of tumor angiogenesis and holds potential as an adjuvant in antiangiogenic strategies, particularly under hypoxic conditions.