Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism.
Vascular recovery or re-angiogenesis after radiotherapy plays a significant role in tumor recurrence, whereas molecular mechanisms of this process remain elusive. In this work, we found that dying glioma cells promoted post-irradiation angiogenesis through a caspase 3 dependent mechanism. Evidence in vitro and in vivo indicated that caspase 3 inhibition undermined proangiogenic effects of dying glioma cells. Proteolytic inactivation of caspase 3 in glioma cells reduced tumorigenicity. Importantly, we identified that NF-κB/COX-2/PGE2axis acted as downstream signaling of caspase 3, mediating proangiogenic response after irradiation. Additionally, VEGF-A, regulated by caspase 3 possibly through phosphorylated eIF4E, was recognized as another downstream factor participating in the proangiogenic response. In conclusion, these data demonstrated that caspase 3 in dying glioma cells supported the proangiogenic response after irradiation by governing NF-κB/COX-2/PGE2axis and p-eIF4E/VEGF-A signaling. While inducing caspase 3 activation has been a generally-adopted notion in cancer therapeutics, our study counterintuitively illustrated that caspase 3 activation in dying glioma cells unfavorably supported post-irradiation angiogenesis. This double-edged role of caspase 3 suggested that taming caspase 3 from the opposite side, not always activating it, may provide novel therapeutic strategies due to restricted post-irradiation angiogenesis.
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Xiao
X
Feng
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Yang
Y
Yu
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Sijia
S
He
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Jin
J
Cheng
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Yanping
Y
Gong
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Zhengxiang
Z
Zhang
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Xuguang
X
Yang
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Bing
B
Xu
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Xinjian
X
Liu
The Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: chuan.li@duke.edu.
Chuan-Yuan
CY
Li
Institute of Translational Medicine and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China. Electronic address: tl09168@hotmail.com.
Ling
L
Tian
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China. Electronic address: qhuang@sjtu.edu.cn.
Qian
Q
Huang
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D010766:Phosphorylation; D015398:Signal Transduction / Q000528:radiation effects; D014162:Transfection; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D061945:Caspase Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D016328:NF-kappa B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D015232:Dinoprostone
Angiogenesis; COX-2/PGE(2); Caspase 3; Irradiation; VEGF-A