14 research outputs found
Zinc Downregulates HIF-1α and Inhibits Its Activity in Tumor Cells In Vitro and In Vivo
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.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.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
Vilna My Vilna: Stories. By Abraham Karpinowitz , trans. Helen Mintz; intro. Justin Cammy. Syracuse: Syracuse University Press, 2015. xxxi, 185 pp. Notes. Bibliography. Glossary. Illustrations. Maps. $24.95, paper.
Russian Idea, Jewish Presence: Essays on Russian-Jewish Intellectual Life. By Brian Horowitz. Brighton: Academic Studies Press, 2013. xvi, 307 pp. Appendix. Notes. Bibliography. Index. Illustrations. $59.00, hard bound.
The Russian-Jewish Tradition: Intellectuals, Historians, Revolutionaries. By Brian Horowitz. Boston: Academic Studies Press, 2017. vii, 282pp. Notes. Bibliography. Index. $82.00, hard bound.
Music from a Speeding Train: Jewish Literature in Post-Revolution Russia. By Harriet Murav. Stanford Studies in Jewish History and Culture. Stanford: Stanford University Press, 2011. xi, 399 pp. Notes. Bibliography. Index. Illustrations. Photographs. $65.00, hard bound.
Nathaniel Deutsch. The Jewish Dark Continent: Life and Death in the Russian Pale of Settlement. Cambridge, MA: Harvard University Press, 2011. 384 pp., map.
Zinc decreases tumor cell invasiveness <i>in vitro</i> and induces HIF-1α downregulation <i>in vivo</i>.
<p>(<b>A</b>) Serum-starved U373MG cells were treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h and cell invasion was measured using a Boyden's chamber invasion assay. Cell invasion results (mean ±S.D.) for quadruplicates from four independent experiments are shown. *, P<0.0001. (<b>B</b>) Serum-starved C27 cells were treated with 100 µM for 24 h, under basal “hypoxic” condition and cell invasion was measured as in (A). Cell invasion results (mean ±S.D.) for quadruplicates from four independent experiments are shown. *, P<0.0001. (<b>C</b>) Representative tumors derived from human U373MG cells transfected with HIF-1α-ODD-luc and pcDNA3-luc control vectors marked with luciferase were imaged using the IVIS imaging system 200 series at day 6 after tumor cell injection and at day 10 following 4 days of zinc daily administration. Four mice/group are shown. (<b>D</b>) RNA samples from explanted tumors, at day 10 after tumor cell injection and after 4 days of zinc treatment, were used for reverse-transcription (RT)-PCR. The mRNA levels were normalized to GAPDH expression. (<b>E</b>) Tissue samples as in (D) were used for Western immunoblotting of VEGF and HIF-1α levels and anti-tubulin and anti-Hsp70 were used, respectively, as protein loading control. Similar results were obtained with different tissue samples.</p