Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells.
Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells.
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DOI：
10.1371/journal.pone.0027112
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jaakkola PM
中科院分区：
文献类型：
--
作者：
Högel H;Rantanen K;Jokilehto T;Grenman R;Jaakkola PM
缺氧限制细胞增殖和细胞周期进展在G1/S界面，但至少癌细胞的亚群可以逃脱的限制。在癌中，缺氧实际上可以选择具有增强的缺氧存活和增加的侵袭性的细胞。细胞氧传感器HIF脯氨酸羟化酶（PHDs）使细胞功能适应降低的环境氧张力。PHD 3同种型在家族成员中显示出最强的低氧上调。我们在头颈部鳞状细胞癌（HNSCC）中检测到PHD 3 mRNA的强表达。PHD 3的表达与缺氧标志基因的表达相关。在HNSCC来源的细胞系中使用siRNA，我们表明特异性抑制癌细胞中的PHD 3表达导致缺氧中细胞存活率降低。PHD 3的丢失，而不是PHD 2的丢失，导致细胞数量显著减少。虽然caspase-3在缺氧早期被激活，但没有检测到凋亡诱导。然而，缺氧PHD 3抑制引起细胞周期进程的阻滞。G1期细胞数增加，S期细胞数减少，表明在PHD 3抑制下G1向S转变受阻。与此一致，在缺氧条件下，PHD 3敲低可降低过度磷酸化的视网膜母细胞瘤蛋白Rb的水平。PHD 3缺失导致细胞周期蛋白依赖性激酶抑制剂p27表达增加，但不导致p21或p16表达增加。数据表明，在缺氧条件下增加的PHD 3表达增强了癌细胞的细胞周期进展和存活。
Hypoxia restricts cell proliferation and cell cycle progression at the G1/S interface but at least a subpopulation of carcinoma cells can escape the restriction. In carcinoma hypoxia may in fact select for cells with enhanced hypoxic survival and increased aggressiveness. The cellular oxygen sensors HIF proline hydroxylases (PHDs) adapt the cellular functions to lowered environmental oxygen tension. PHD3 isoform has shown the strongest hypoxic upregulation among the family members. We detected a strong PHD3 mRNA expression in tumors of head and neck squamous cell carcinoma (HNSCC). The PHD3 expression associated with expression of hypoxic marker gene. Using siRNA in cell lines derived from HNSCC we show that specific inhibition of PHD3 expression in carcinoma cells caused reduced cell survival in hypoxia. The loss of PHD3, but not that of PHD2, led to marked cell number reduction. Although caspase-3 was activated at early hypoxia no induction of apoptosis was detected. However, hypoxic PHD3 inhibition caused a block in cell cycle progression. Cell population in G1 phase was increased and the population in S phase reduced demonstrating a block in G1 to S transition under PHD3 inhibition. In line with this, the level of hyperphosphorylated retinoblastoma protein Rb was reduced by PHD3 knock-down in hypoxia. PHD3 loss led to increase in cyclin-dependent kinase inhibitor p27 expression but not that of p21 or p16. The data demonstrated that increased PHD3 expression under hypoxia enhances cell cycle progression and survival of carcinoma cells.
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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：
11.5
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Jokilehto, T;Rantanen, K;Jaakkola, PM
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Jaakkola, PM
影响因子：
8
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影响因子：
5.3
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通讯作者：
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影响因子：
4.8
作者：
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Frelin, C