Zinc Downregulates HIF-1α and Inhibits Its Activity in Tumor Cells In Vitro and In Vivo
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{"title"=>"Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo", "type"=>"journal", "authors"=>[{"first_name"=>"Lavinia", "last_name"=>"Nardinocchi", "scopus_author_id"=>"17343906800"}, {"first_name"=>"Valentina", "last_name"=>"Pantisano", "scopus_author_id"=>"37079554200"}, {"first_name"=>"Rosa", "last_name"=>"Puca", "scopus_author_id"=>"17344525100"}, {"first_name"=>"Manuela", "last_name"=>"Porru", "scopus_author_id"=>"35176329300"}, {"first_name"=>"Aurora", "last_name"=>"Aiello", "scopus_author_id"=>"24478661200"}, {"first_name"=>"Annalisa", "last_name"=>"Grasselli", "scopus_author_id"=>"23027591500"}, {"first_name"=>"Carlo", "last_name"=>"Leonetti", "scopus_author_id"=>"7004669245"}, {"first_name"=>"Michal", "last_name"=>"Safran", "scopus_author_id"=>"7005486563"}, {"first_name"=>"Gideon", "last_name"=>"Rechavi", "scopus_author_id"=>"7004955283"}, {"first_name"=>"David", "last_name"=>"Givol", "scopus_author_id"=>"7006011757"}, {"first_name"=>"Antonella", "last_name"=>"Farsetti", "scopus_author_id"=>"6701792214"}, {"first_name"=>"Gabriella", "last_name"=>"D'Orazi", "scopus_author_id"=>"6701432532"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"361026088", "sgr"=>"78650797956", "issn"=>"19326203", "pmid"=>"21179202", "scopus"=>"2-s2.0-78650797956", "doi"=>"10.1371/journal.pone.0015048"}, "id"=>"61f2ed6e-8622-3566-9dbb-bbd382902683", "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.\\n\\nMETHODOLOGY/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.\\n\\nCONCLUSIONS/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.", "link"=>"http://www.mendeley.com/research/zinc-downregulates-hif1%CE%B1-inhibits-activity-tumor-cells-vitro-vivo-1", "reader_count"=>29, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Materials Science"=>1, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Sports and Recreations"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/812598"], "description"=>"<p>(<b>A, upper panel</b>) U373MG glioblastoma cells were transfected with VEGF-luc reporter and 16 h thereafter treated with 100 µM ZnCl<sub>2</sub> and 2% O<sub>2</sub> for, respectively 24 and 16 h, before luciferase activity was assayed. Data are the mean ±S.D. of three independent experiments performed in duplicate. RLU: relative luciferase unit. *, P<0.005. (<b>A, lower panel</b>) Total cell extracts of cells treated as above were assayed for Western immunoblotting. Anti-tubulin was used as protein loading control. (<b>B</b>) U373MG glioblastoma cells were transfected with VEGF-luc reporter and 16 h thereafter treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h, before luciferase activity was assayed. Data are the mean ±S.D. of three independent experiments performed in duplicate. RLU: relative luciferase unit. *, P<0.005. (<b>B, lower panel</b>) Total cell extracts of cells treated as in (A) for Western immunoblotting. (<b>C</b>) Total mRNAs were reverse transcribed from U373MG cells treated as in (A), for semi-quantitative RT-PCR analysis of VEGF expression. Aldolase (ald-A) was used as internal control. (<b>D</b>) Total mRNAs were reverse transcribed from U373MG cells treated as in (B), for semi-quantitative RT-PCR analysis of VEGF expression. Aldolase (ald-A) was used as internal control. (<b>E</b>) Serum-starved U373MG cells were cultured for 24 h with 100 µM ZnCl<sub>2</sub>, and cell conditioned media were analyzed by ELISA assay for VEGF secretion. ELISA results (mean ±S.D.) for duplicates from four independent experiments are shown. *, P<0.005 compared with the untreated control. (<b>F</b>) HUVECs were incubated at 37°C on Matrigel with CM form U373MG cells untreated or treated with ZnCl<sub>2</sub> (100 µM) in normoxia or under hypoxia (CoCl<sub>2</sub> 200 µM for 24 h). The number of tube networks from triplicate wells (10 fields/well) was quantified at ×20 magnification after 3 hours of differentiation. (<b>G</b>) 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 nuclear cell extracts were assayed for Western immunoblotting. Anti-Hsp70 was used as protein loading control. (<b>H</b>) U373MG cells were transfected with HIF-1α dominant negative vector (DN-HIF-1α, 2 µg) and 16 h after transfection treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h. Luciferase activity was assayed 36 h thereafter and normalized by β-galactosidase activity. Data represent mean ±S.D. of three independent experiments performed in duplicate. *, P<0.001.</p>", "links"=>[], "tags"=>["zinc", "hif-1-induced", "vegf", "glioblastoma"], "article_id"=>482936, "categories"=>["Cancer", "Chemistry"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015048.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_zinc_on_HIF_1_induced_VEGF_in_glioblastoma_and_tube_formation_/482936", "title"=>"Effect of zinc on HIF-1-induced VEGF in glioblastoma and tube formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:50:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/812724"], "description"=>"<p>(<b>A</b>) Proliferating C38 and C27 prostate cancer cells were treated with 100 µM ZnCl<sub>2</sub> and 2% O<sub>2</sub> for, respectively 24 and 16 h. Equal amount of nuclear cell extracts were assayed for Western immunoblotting. Anti-Hsp70 was used as protein loading control. (<b>B</b>) Proliferating C38 and C27 prostate cancer cells were treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h. Equal amount of nuclear cell extracts were assayed for Western immunoblotting. Anti-Hsp70 was used as protein loading control. (<b>C</b>) ChIP analysis with anti-HIF-1α antibody or no antibody as control was performed in C38 cells treated with 100 µM ZnCl<sub>2</sub> and 2% O<sub>2</sub> for, respectively 24 and 16 h and in C27 cells treated with100 µM ZnCl<sub>2</sub> for 24 h under basal “hypoxic” condition. Recruitment of HIF-1α onto the VEGF promoter was detected by qRT-PCR, using primers spanning the HRE region. Relative enrichment of HIF-1α compared to no antibody onto VEGF promoter is shown. The data represent the mean of 2 independent experiments ±S.D. (<b>D, upper panel</b>) C38 and C27 cells were transfected with VEGF-luc reporter and 16 h after transfection treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h, before luciferase activity was assayed. Data represent the mean ±S.D. of three independent experiments performed in duplicate. RLU: relative luciferase unit. *, P<0.005. (<b>D, lower panel</b>) Total mRNAs were reverse transcribed from C38 and C27 cells treated as above for semi-quantitative RT-PCR analyses of HIF-1 target genes. Aldolase (ald-A) is shown as internal control.</p>", "links"=>[], "tags"=>["destabilization", "inhibition", "hif-1", "transcriptional"], "article_id"=>483080, "categories"=>["Cancer", "Chemistry"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015048.g002", "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIFs_945_destabilization_and_inhibition_of_HIF_1_transcriptional_activity_by_zinc_/483080", "title"=>"HIFs-α destabilization and inhibition of HIF-1 transcriptional activity by zinc.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:51:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/812851"], "description"=>"<p>(<b>A</b>) C38 and C27 cells were treated with 100 µM ZnCl<sub>2</sub> for 24 h in the presence or absence of 10 µM proteasome inhibitor MG132 for 4 h, under hypoxia (200 µM CoCl<sub>2</sub> for 16 h) for C38 cells and in basal “hypoxic” condition for C27 cells. Equal amount of nuclear cell extracts were assayed for Western immunoblotting. Anti-Hsp70 was used as a protein loading control. (<b>B</b>) 293 cells were transfected with HIF-1α-ODD-luc vector and 16 h after transfection treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h, before luciferase activity was assayed. Data represent the mean ±S.D. of three independent experiments performed in duplicate. RLU: relative luciferase unit. *, P<0.005. (<b>C</b>) C38 cells were transfected with either HIF-1α-Flag expression vector or the HIF-1αP402/P564A-Flag mutant and 16 h after transfection treated with 100 µM ZnCl<sub>2</sub> for 24 h and 2% O<sub>2</sub> or 200 µM CoCl<sub>2</sub> for 16 h. Equal amount of nuclear cell extracts were assayed for Western immunoblotting with anti-Flag antibody. (<b>D</b>) C38 cells were treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h, in the presence of 10 µM proteasome inhibitor MG132 for 4 h. Equal amount of total cell extracts were immunoprecipitated with anti-HIF-1α antibody and then assayed for Western immunoblotting to detect pVHL interaction. Inputs represent 1/10 of total cell extracts used for immunoprecipitation. (<b>E</b>) RCC4 VHL-null renal carcinoma cells were treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h. Equal amount of nuclear cell extracts were assayed for Western immunoblotting. Anti-Hsp70 was used as protein loading control. (<b>F</b>) RCC4 VHL-null renal carcinoma cells were transfected with VEGF-luc reporter and 16 h after transfection treated with 100 µM ZnCl<sub>2</sub> and 200 µM CoCl<sub>2</sub> for, respectively 24 and 16 h, before luciferase activity was assayed. Data represent the mean ±S.D. of three independent experiments performed in duplicate. RLU: relative luciferase unit. In the lower panel, total mRNAs were reverse transcribed from RCC4 cells for semi-quantitative RT-PCR analysis of VEGF. Aldolase (ald-A) was used as internal control.</p>", "links"=>[], "tags"=>["induces", "proteasomal"], "article_id"=>483213, "categories"=>["Cancer", "Chemistry"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015048.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Zinc_induces_HIF_1_945_proteasomal_degradation_/483213", "title"=>"Zinc induces HIF-1α proteasomal degradation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/813000"], "description"=>"<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>", "links"=>[], "tags"=>["decreases", "invasiveness", "induces", "downregulation"], "article_id"=>483357, "categories"=>["Cancer", "Chemistry"], "users"=>["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"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015048.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Zinc_decreases_tumor_cell_invasiveness_in_vitro_and_induces_HIF_1_downregulation_in_vivo_/483357", "title"=>"Zinc decreases tumor cell invasiveness <i>in vitro</i> and induces HIF-1α downregulation <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:52:40"}

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