Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo.
Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo.
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DOI：
10.1371/journal.pone.0015048
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发表时间：
2010-12-13
期刊：
影响因子：
3.7
通讯作者：
D'Orazi G
中科院分区：
文献类型：
--
作者：
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
缺氧诱导因子-1α(HIF-1α)是缺氧诱导的基因表达变化的主要原因，也是肿瘤进展过程中的血管生成开关。低氧诱导因子-1α在肿瘤中表达上调，导致肿瘤生长更具侵袭性和化疗耐药性，因此是抗肿瘤干预的重要靶点。我们此前曾报道，锌下调了HIF-1α的水平。在此，我们评估了锌诱导缺氧诱导因子-1α下调的分子机制，以及锌是否也在体内影响了缺氧诱导因子-1α的表达。在这里，我们报告锌在低氧条件下下调人前列腺癌和胶质母细胞瘤细胞中HIF-1α蛋白水平，无论是诱导性的还是结构性的。对其分子机制的研究表明，锌诱导的HIF-1α蛋白酶体降解可被蛋白酶体抑制剂MG132阻止。锌对人肾癌细胞系RCC4VHL缺失型HIF-1α表达下调无效，突变株HIF-1αP402/P564A对锌处理耐药。与HIF-1α类似，锌也下调缺氧诱导的HIF-2α，而HIF-1β亚单位无明显变化。锌抑制血管内皮生长因子启动子上的α募集，锌诱导的血管内皮生长因子依赖的活化与胶质母细胞瘤和前列腺癌细胞体外侵袭力的降低有关。最后，通过生物发光成像，锌在体内下调了缺氧诱导因子-1α的水平，并抑制了肿瘤内血管内皮生长因子的表达。这些发现表明，锌可以诱导HIF-1α蛋白酶体的降解，表明锌可以作为人类肿瘤中HIF-1α的抑制剂，以抑制与肿瘤进展有关的重要途径，如由血管内皮生长因子、mdr1和bcl2靶基因诱导的途径，并有望加强抗癌治疗。
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.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
2.2
作者：
FALK, W;GOODWIN, RH;LEONARD, EJ
通讯作者：
LEONARD, EJ
影响因子：
21.3
作者：
Calzado, Marco A.;de la Vega, Laureano;Schmitz, M. Lienhard
通讯作者：
Schmitz, M. Lienhard
DOI：
10.1016/j.bbamcr.2008.10.013
发表时间：
2009-02-01
影响因子：
5.1
作者：
Nardinocchi, Lavinia;Puca, Rosa;D'Orazi, Gabriella
通讯作者：
D'Orazi, Gabriella
影响因子：
4.3
作者：
Nardinocchi, Lavinia;Puca, Rosa;D'Orazi, Gabriella
通讯作者：
D'Orazi, Gabriella