Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF-1alpha.
Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF-1alpha.
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DOI：
10.1371/journal.pone.0006819
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发表时间：
2009-08-28
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;Puca R;Sacchi A;Rechavi G;Givol D;D'Orazi G
通过磷酸化丝氨酸46 （Ser46）的肿瘤抑制因子同源结构域相互作用蛋白激酶2 （HIPK2）是p53凋亡功能的关键调节因子。HIPK2也是抑制肿瘤血管生成和化疗耐药的缺氧诱导因子-1α (HIF-1α)的转录共抑制因子。HIPK2可以通过包括缺氧在内的多种机制在肿瘤中失调。在这里，我们试图通过恢复HIPK2功能和抑制HIF-1α来靶向缺氧，以便为HIPK2和p53参与对抗缺氧诱导的化疗耐药提供证据。当结肠癌和肺癌细胞暴露于低氧或钴缺氧时，HIPK2功能受损，导致HIF-1α表达增加，抑制p53对药物的凋亡反应。钴抑制HIPK2在HIF-1α启动子上的募集。缺氧诱导p53靶细胞MDM2表达下调HIPK2，通过siRNA抑制MDM2恢复HIPK2/p53Ser46对药物的应答。在缺氧处理的细胞中补充锌可以增加HIPK2蛋白的稳定性和核积累，从而恢复HIPK2与HIF-1α启动子的结合，抑制MDR1、Bcl2和VEGF基因，激活p53对药物的凋亡反应。锌与ADR联用通过抑制HIF-1通路和上调p53凋亡靶基因，在体内强烈抑制肿瘤生长。我们在这里首次发现，锌可以抵消缺氧诱导的HIPK2失调，恢复HIPK2对HIF-1通路的抑制，并重新激活p53对药物的凋亡反应，强调了锌补充剂与化疗联合使用的潜在应用，以解决缺氧问题并改善肿瘤治疗。
The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1α (HIF-1α) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1α, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance. Upon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1α expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1α promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1α promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes. We show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment.
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影响因子：
8
作者：
Di Stefano, V;Blandino, G;D'Orazi, G
通讯作者：
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影响因子：
21.3
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DOI：
10.1016/j.bbamcr.2008.10.013
发表时间：
2009-02-01
影响因子：
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作者：
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通讯作者：
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影响因子：
8
作者：
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DOI：
10.1016/s0027-5107(99)00162-1
发表时间：
1999-12-17
影响因子：
2.3
作者：
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