The HIF-1α/VEGF signaling axis mediates resveratrol-induced inhibition of prostate cancer cell proliferation and angiogenesis

Purpose Resveratrol has been proposed as a promising candidate for prostate cancer therapy; however, its role in regulating tumor angiogenesis and progression remains incompletely elucidated. This study aimed to investigate the effects of resveratrol on prostate cancer progression and the involvement of the HIF-1α/VEGF axis. Methods PC-3 cells were cultured under chemical hypoxia induced by CoCl 2 , and HIF-1α overexpression was used as a rescue approach. Human umbilical vein endothelial cells (HUVECs) were exposed to tumor-conditioned medium. PC-3 xenograft models were then established to evaluate tumor growth and angiogenesis. Key endpoints included cell viability, HIF-1α and VEGF expression, microvessel density (MVD), matrix metalloproteinase levels, and body weight changes as a preliminary safety indicator. Results Under hypoxic conditions, resveratrol significantly inhibited prostate cancer cell viability and clonogenic capacity by suppressing HIF-1α transcriptional activity and downstream VEGF expression. In human umbilical vein endothelial cells (HUVECs) exposed to tumor-conditioned medium, reduced VEGF levels were associated with decreased phosphorylated VEGFR2 (p-VEGFR2) and matrix metalloproteinase-2 (MMP2), accompanied by impaired tubule formation and cell migration—a phenotype comparable to that induced by the HIF-1α inhibitor YC-1. Crucially, HIF-1α overexpression reversed these inhibitory effects on VEGF release and vascular function, supporting a pathway-dependent mechanism of resveratrol. In PC-3 xenograft models, resveratrol treatment reduced tumor volume by 55.4% and decreased Ki-67 positive staining, indicating suppressed proliferation, without inducing significant body weight loss, suggesting a favorable safety profile. Furthermore, in vivo analyses revealed that resveratrol downregulated intratumoral HIF-1α and VEGF, reduced CD31-positive MVD, and lowered intratumoral MMP9 levels. Conclusion Resveratrol appears to inhibit prostate cancer growth and angiogenesis by targeting the HIF-1α/VEGF signaling axis. These findings support further preclinical evaluation of resveratrol as a candidate modulator of HIF-1α/VEGF-associated prostate-cancer angiogenesis, while additional pharmacokinetic, toxicological, and efficacy studies are required before therapeutic translation.