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

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 mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. 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 were investigated. The role of duanyu1531δ was further verified in human colorectal tumor specimens. RESULTS:Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened duanyu1531δ cleavage. Both DN_duanyu1531δ and duanyu1531δ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3-, caspase-7-, or tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in 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 duanyu1531δ in colorectal tumor specimens was associated with worse patient prognosis. CONCLUSIONS:The axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.

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