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

Lavinia Nardinocchi, Valentina Pantisano, Rosa Puca, Manuela Porru, Aurora Aiello, Annalisa Grasselli, Carlo Leonetti, Michal Safran, Gideon Rechavi, David Givol, Antonella Farsetti, Gabriella D'Orazi

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Abstract

Background: Hypoxia inducible factor-1α (HIF-1α) is responsible for the majority of HIF-1-induced gene expression changes under hypoxia and for the "angiogenic switch" during tumor progression. HIF-1α 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-1α levels. Here, we evaluated the molecular mechanisms of zinc-induced HIF-1α downregulation and whether zinc affected HIF-1α also in vivo. Methodology/Principal Findings: Here we report that zinc downregulated HIF-1α 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-1α proteasomal degradation that was prevented by treatment with proteasomal inhibitor MG132. HIF-1α downregulation induced by zinc was ineffective in human RCC4 VHL-null renal carcinoma cell line; likewise, the HIF-1αP402/P564A mutant was resistant to zinc treatment. Similarly to HIF-1α, zinc downregulated also hypoxia-induced HIF-2α whereas the HIF-1β subunit remained unchanged. Zinc inhibited HIF-1α 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-1α levels in vivo, by bioluminescence imaging, and suppressed intratumoral VEGF expression. Conclusions/Significance: These findings, by demonstrating that zinc induces HIF-1α proteasomal degradation, indicate that zinc could be useful as an inhibitor of HIF-1α 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.

Original languageEnglish
Article numbere15048
JournalPLoS One
Volume5
Issue number12
DOIs
Publication statusPublished - 2010

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nardinocchi, L., Pantisano, V., Puca, R., Porru, M., Aiello, A., Grasselli, A., Leonetti, C., Safran, M., Rechavi, G., Givol, D., Farsetti, A., & D'Orazi, G. (2010). Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo. PLoS One, 5(12), [e15048]. https://doi.org/10.1371/journal.pone.0015048