Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.
Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.
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DOI：
10.1042/bst20200861
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发表时间：
2021-06-30
影响因子：
3.9
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Bolland H;Ma TS;Ramlee S;Ramadan K;Hammond EM
缺氧是大多数实体瘤的特征，并预示预后不良。在放射生物学缺氧（<0.1%O2）中，细胞对辐射的抵抗力提高了三倍。对放射生物学缺氧的生物学反应是激活未折叠蛋白和DNA损伤反应（UPR和DDR）的少数生理相关应激之一。在常氧条件下进行的研究中已经确定了这些途径之间的联系。部分基于这些以前的研究和我们实验室最近的工作，我们假设对缺氧的生物反应可能包括DDR和UPR之间的重叠。虽然抑制DDR是改善辐射反应的公认策略，但通过针对普遍定期审议实现这一目标的可能性尚未实现。我们进行了一项系统的回顾，以确定DDR和UPR之间的联系，在人类细胞系暴露于<2%的O2。根据PRISMA指南，通过奥维德MEDLINE检索2010年1月至2020年10月的文献并进行评价。共纳入202项研究。LAMP 3、ULK 1、TRIB 3、CHOP、NOXA、NORAD、SIAH 1/2、DYRK 2、HIPK 2、CREB、NUPR 1、JMJD 2B、NRF 2、GSK-3B、GADD 45 a、GADD 45 b、STAU 1、C-SRC、HK 2、CAV 1、CypB、CLU、IGFBP-3和SP1被强调为低氧DDR和UPR之间的潜在联系。总体而言，我们发现很少有研究表明DDR和UPR在缺氧中存在分子联系，然而，很明显，许多突出的分子需要在放射生物学缺氧下进行进一步研究，因为这些分子可能包括新的治疗靶点，以改善放射治疗反应。
Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to radiation. The biological response to radiobiological hypoxia is one of few physiologically relevant stresses that activates both the unfolded protein and DNA damage responses (UPR and DDR). Links between these pathways have been identified in studies carried out in normoxia. Based in part on these previous studies and recent work from our laboratory, we hypothesised that the biological response to hypoxia likely includes overlap between the DDR and UPR. While inhibition of the DDR is a recognised strategy for improving radiation response, the possibility of achieving this through targeting the UPR has not been realised. We carried out a systematic review to identify links between the DDR and UPR, in human cell lines exposed to <2% O2. Following PRISMA guidance, literature from January 2010 to October 2020 were retrieved via Ovid MEDLINE and evaluated. A total of 202 studies were included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 and SP1 were highlighted as potential links between the hypoxic DDR and UPR. Overall, we identified very few studies which demonstrate a molecular link between the DDR and UPR in hypoxia, however, it is clear that many of the molecules highlighted warrant further investigation under radiobiological hypoxia as these may include novel therapeutic targets to improve radiotherapy response.