title: 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.
  
  
  RESULTS
  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
  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.affiliation: Molecular Oncogenesis Laboratory, Department of Experimental Oncology, National Cancer Institute Regina Elena, Rome, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Nardinocchi
authors.forename: Valentina
authors.initials: V
authors.lastname: Pantisano
authors.forename: Rosa
authors.initials: R
authors.lastname: Puca
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Aurora
authors.initials: A
authors.lastname: Aiello
authors.forename: Annalisa
authors.initials: A
authors.lastname: Grasselli
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Michal
authors.initials: M
authors.lastname: Safran
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: David
authors.initials: D
authors.lastname: Givol
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D015032:Zinc / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D046988:Proteasome Endopeptidase Complex; D015032:Zinc