Oncotarget

Priority Research Papers:

Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis

Xiao Feng _, Ling Tian, Zhengxiang Zhang, Yang Yu, Jin Cheng, Yanping Gong, Chuan-Yuan Li and Qian Huang

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Oncotarget. 2015; 6:32353-32367. https://doi.org/10.18632/oncotarget.5898

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Abstract

Xiao Feng1,*, Ling Tian2,*, Zhengxiang Zhang1, Yang Yu1, Jin Cheng1, Yanping Gong1, Chuan-Yuan Li3 and Qian Huang1

1 The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2 Experimental Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3 The Department of Dermatology, Duke University Medical Center, Durham, NC, USA

* These authors have contributed equally to this work

Correspondence to:

Qian Huang, email:

Chuan-Yuan Li, email:

Keywords: X-irradiation, dying tumor cells, caspase 3, VEGF-A, angiogenesis

Received: August 04, 2015 Accepted: September 17, 2015 Published: September 29, 2015

Abstract

Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA.


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