Zinc downregulates HIF-1alpha and inhibits its activity in tumor cells in vitro and in vivo.

Background: Hypoxia inducible factor-1a (HIF-1a) is responsible for the majority of HIF-1-induced gene expression changes
under hypoxia and for the ''angiogenic switch'' during tumor progression. HIF-1a is often upregulated in tumors leading to
more aggressive tumor growth and chemoresistance, therefore representing an important target for antitumor
intervention. We previously reported that zinc downregulated HIF-1a levels. Here, we evaluated the molecular mechanisms
of zinc-induced HIF-1a downregulation and whether zinc affected HIF-1a also in vivo.
Methodology/Principal Findings: Here we report that zinc downregulated HIF-1a protein levels in human prostate cancer
and glioblastoma cells under hypoxia, whether induced or constitutive. Investigations into the molecular mechanisms
showed that zinc induced HIF-1a proteasomal degradation that was prevented by treatment with proteasomal inhibitor
MG132. HIF-1a downregulation induced by zinc was ineffective in human RCC4 VHL-null renal carcinoma cell line; likewise,
the HIF-1aP402/P564A mutant was resistant to zinc treatment. Similarly to HIF-1a, zinc downregulated also hypoxia-induced
HIF-2a whereas the HIF-1b subunit remained unchanged. Zinc inhibited HIF-1a recruitment onto VEGF promoter and the
zinc-induced suppression of HIF-1-dependent activation of VEGF correlated with reduction of glioblastoma and prostate
cancer cell invasiveness in vitro. Finally, zinc administration downregulated HIF-1a levels in vivo, by bioluminescence
imaging, and suppressed intratumoral VEGF expression.
Conclusions/Significance: These findings, by demonstrating that zinc induces HIF-1a proteasomal degradation, indicate
that zinc could be useful as an inhibitor of HIF-1a in human tumors to repress important pathways involved in tumor
progression, such as those induced by VEGF, MDR1, and Bcl2 target genes, and hopefully potentiate the anticancer
therapies.