36P - Radiotherapy-induced apoptotic tumor cells stimulate proliferation of living tumor cells via caspase 3/7–PKC&dgr;–Akt/p38 MAPK pathway

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Basic Science
Surgery and/or Radiotherapy of Cancer
Presenter Jin Cheng
Citation Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362
Authors J. Cheng1, L. Tian2, Q. Huang1
  • 1The Comprehensive Cancer Center And Shanghai Key Laboratory For Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201600 - Shanghai/CN
  • 2Institute Of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201600 - Shanghai/CN

Abstract

Background

Our previous studies demonstrated that radiotherapy-induced apoptotic cells significantly stimulate the proliferation of surviving tumor cells through the caspase 3-iPLA2-AA-PGE2 pathway. However, the molecular events involved in this stimulation seem to involve in different pathways. This study seeks to investigate the molecular mechanisms involved in the stimulatory role of apoptotic human pancreatic (Panc1) and colonic cancer (HT29) cells in vitro.

Methods

Apoptotic Panc1 and HT29 cells were produced as feeders by 10Gy X-ray radiation. Caspase 3, 7, PKC&dgr;, Akt, p38 MAPK and JNK1/2 activation was detected by Western blot. Panc1 and HT29 cells stably transduced by firefly luciferase and green fluorescent protein fusion gene (Panc1-Fluc and HT29-Fluc) were used as reporter. Living Panc1-Fluc and HT29-Fluc cells proliferation on radiated Panc1 and HT29 cells were evaluated by luciferase activity using bioluminescence imaging.

Results

The presence of apoptotic Panc1 and HT29 cells significantly stimulated the proliferation of living Panc1-Fluc and HT29-Fluc cells. These apoptotic tumor cells showed significantly increased caspase 3 and 7 as well as PKC&dgr; activity. However, significant decrease of the stimulation effect on living Panc1-Fluc and HT29-Fluc cells was observed when apoptotic Panc1 and HT29 cells stably transduced by either dominant-negative caspase 3, caspase 7 or PKC&dgr; were used as feeders instead; and pan PKC inhibitor and specific PKC&dgr; inhibitor significantly inhibited the stimulatory effect of apoptotic Panc1 and HT29 cells. Additionally, significantly increased phosphorylation of Akt, p38 MAPK and JNK1/2 were observed in the irradiated Panc1 and HT29 cells. Interestedly, dominant-negative PKC&dgr; was resistant to the cleavage and activation by caspase 3 or 7 and the expression of dominant-negative PKC&dgr; attenuated radiation induced Akt phosphorylation in both Panc1 and HT29 cells, attenuated p38 MAPK activation in Panc1 cells.

Conclusions

Apoptotic tumor cells can significantly stimulate the proliferation of living tumor cells through the caspase 3/7-PKC&dgr;-Akt/p38 MAPK pathway after radiotherapy.

Clinical trial identification

Legal entity responsible for the study

Qian Huang, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Funding

National Natural Science Foundation (81120108017, 81172030) and National Basic Research Program of China (2010CB529902)

Disclosure

All authors have declared no conflicts of interest.