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http://purl.uniprot.org/citations/30890550http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30890550http://www.w3.org/2000/01/rdf-schema#comment"

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 Cδ (DN_PKCδ) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKCδ 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 PKCδ were investigated. The role of PKCδ was further verified in human colorectal tumor specimens.

Results

Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKCδ cleavage. Both DN_PKCδ and PKCδ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3-, caspase-7-, or PKCδ-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in PKCδ- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1α, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKCδ in colorectal tumor specimens was associated with worse patient prognosis.

Conclusions

The caspase-3/PKCδ/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.org/dc/terms/identifier"doi:10.1158/1078-0432.ccr-18-3001"xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Cheng J."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"He S."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Feng X."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Gong Y."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Li C."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Huang Q."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Luo Y."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Liu X."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Ma J."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Wang Y."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Zhou L."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Wang M."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Sun L."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Zhang Z."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Zhao M."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Zhang S."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Yu Y."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Tian L."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/author"Dai C."xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/name"Clin Cancer Res"xsd:string
http://purl.uniprot.org/citations/30890550http://purl.uniprot.org/core/pages"3732-3743"xsd:string
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