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Clin Cancer Res. 2019 Jun 15;25(12):3732-3743. doi: 10.1158/1078-0432.CCR-18-3001. Epub 2019 Mar 19.

The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy.

Author information

1
Molecular Diagnostic Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3
Department of General Surgery, Shanghai Fourth People's Hospital, Shanghai, China.
4
Department of Pharmacy, The First Affiliated Hospital, School of Medicine, Soochow University, Suzhou, China.
5
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6
Department of Dermatology, Duke University Medical Center, Durham, North Carolina.
7
Department of Dermatology, Duke University Medical Center, Durham, North Carolina. huangqian_sjtu@163.com chuan.li@duke.edu.
8
Molecular Diagnostic Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. huangqian_sjtu@163.com chuan.li@duke.edu.
#
Contributed equally

Abstract

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.

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