Zinc as a Dual-Condition Inhibitor of HIF-1α/VEGF-α–Mediated Angiogenesis in Clear Cell Renal Carcinoma
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Keywords
Angiogenesis, clear cell renal carcinoma, HIF-1α, Hypoxia, Zinc
Abstract
Clear cell renal cell carcinoma (ccRCC) is marked by aberrant hypoxia-driven signaling and enhanced angiogenesis mediated by hypoxia-inducible 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 transcrip-tional 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.
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Beatriz Miquilino Neto, Radiation Technology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil
Radiation Technology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.
Luiz Felipe S. Teixeira, Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil
Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.
Amanda Sena de Sousa, Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil
Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.
Monica Beatriz Mathor, Radiation Technology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil
Radiation Technology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.
Maria Helena Bellini Marumo, Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil
Biotechnology Center, Nuclear and Energy Research Institute (IPEN/CNEN), São Paulo, Brazil.