In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 12 ( 2019-06-15), p. 3732-3743
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-18-3001
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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