title: Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis.
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.
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Feng
authors.affiliation: Experimental Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: The Department of Dermatology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061945:Caspase Inhibitors; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: VEGF-A; X-irradiation; angiogenesis; caspase 3; dying tumor cells