The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy
The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy
复制标题
Caspase-3/PKCd/Akt/VEGF-A 信号通路介导放射治疗期间的肿瘤增殖
DOI：
10.1158/1078-0432.ccr-18-3001
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发表时间：
2019-06-15
影响因子：
11.5
通讯作者：
Huang, Qian
中科院分区：
文献类型：
--
作者：
Cheng, Jin;He, Sijia;Huang, Qian
目的：肿瘤再生长是放射治疗失败和/或肿瘤复发的主要原因。其潜在机制尚不清楚。我们先前的研究表明，辐射诱导的凋亡细胞介导了肿瘤的再增殖，其中caspase-3起着重要的作用。实验设计：构建了caspase-3不能被caspase-3切割并不能被辐射诱导的细胞凋亡所激活的显性负性蛋白激酶C增量(DN_PKC Delta)突变体。在体外和体内肿瘤再生长模型中，比较了稳定转导DNPKC Delta的肿瘤细胞和野生型肿瘤细胞的生长促进作用。研究了caspase-3和PKC Delta的下游效应。结果：caspase-3或caspase-7的失活可抑制肿瘤的再生长，减弱PKC Delta的切割。DNPKC Delta和PKC Delta抑制剂在体外和体内均能抑制肿瘤的再生长。在caspase-3-、caspase-7-或PKC Delta失活的肿瘤细胞中，磷酸化Akt被减弱。此外，在WPKC Delta或Akt灭活的肿瘤细胞中，血管内皮生长因子(VEGF)-A而不是低氧诱导因子1α(HIF1α)的表达减少。此外，抑制p-Akt、HIF1α、血管内皮生长因子-A或血管内皮生长因子-A受体显著减少肿瘤再生长。结论：caspase-3/PKC Delta/Akt/VEGF-A轴参与了肿瘤的再生长，可作为提高放疗疗效的潜在靶点。
Purpose: Tumor repopulation is known as a major cause of treatment failure and/or tumor recurrence after radiotherapy. The underlying mechanism remains unclear. Our previous study demonstrated that irradiated apoptotic cells mediated tumor repopulation, in which caspase-3 played an important role. Herein, we investigated downstream effectors of caspase-3 involved in this process.Experimental Design: A dominant-negative protein kinase C delta (DN_PKC delta) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKC delta stably transduced tumor cells were compared with wild-type tumor cells for their growth stimulation effects in in vitro and in vivo tumor repopulation models. Downstream effectors of caspase-3 and PKC delta were investigated. The role of PKC delta was further verified in human colorectal tumor specimens.Results: Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKC delta cleavage. Both DN_PKC delta and PKC delta inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3-, caspase-7-, or PKC delta-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1 alpha (HIF1 alpha) was decreased in WPKC delta- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1 alpha, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKC delta in colorectal tumor specimens was associated with worse patient prognosis.Conclusions: The caspase-3/PKC delta/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.