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

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 5 Issue 12 Pg. e15048 (Dec 13 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 21179202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• Proteasome Endopeptidase Complex
• Zinc

Topics

• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (metabolism)
• Cell Line
• Cell Line, Tumor
• Disease Progression
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Glioblastoma (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• In Vitro Techniques
• Male
• Prostatic Neoplasms (metabolism)
• Proteasome Endopeptidase Complex (pharmacology)
• Vascular Endothelial Growth Factor A (biosynthesis)
• Zinc (pharmacology)