Ruijin Hospital, Shanghai Jiaotong University School of Medicine Shanghai, Shanghai
Y. Lin, J. Zhao, and K. Liao; Department of Radiation Oncology, Ruijin Hospital, Shang- hai Jiao Tong University School of Medicine, shanghai, China
Purpose/Objective(s): Neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis and malignancy across a host of cancers. Recent studies highlight bidirectional signalling between tumours and neurons; however, the communications between tumour and neurons on response to radiotherapy remains obscure, which hampers the development of predictive assays and strategies to targeted radio-therapy. Materials/
Methods: To determine the specific bidirectional signaling between tumor and neurons, glioblastoma orgnoids (GBOs) and classic tumor cell lines were co-cultured with neurons. And the degree of neuronal senescence and GBO mortality were detected upon radiotherapy. Targeted metabolomics on supernatants derived from irradiated GBOs was performed to find out the specific substances that tumor secreted to induce neuronal senescence. RNA pulldown and IP-MS were used to explore the specific signal pathway that tumor cell regulating neuronal senescence. Further, transcriptome sequencing of irradiated neurons with or without co-cultured with GBOs was performed to uncover molecules changed in neurons during this process. Results: Tumor recruited and induced neuronal senescence upon irradiation through elevated concentration of prostaglandin E2 (PGE2). Senescent neuron promoted tumor survival in turn. The mechanistic studies revealed that irradiation triggered asparagine endopeptidase (AEP) enzymatically cleaves eIF4A1 at amino acid N139. Truncated eIF4A1-C promotes mRNA stability of PTGES3, an enzyme participating in PGE2 synthesis, via increased binding to EIF4A3 and unable combine to DDX6 because of lacking N terminal of eIF4A1. Increased PGE2 further enhanced tumor AEP expression at long-duration via CEBPß activation. Knockdown of AEP significantly decreased tumor progression in animal models while recue teIF4A1-C in AEP-KD tumor cells reverses this phenomenon. Moreover, targeting AEP or PGE2 significantly reduces neuronal senescence and sensitizes tumor to radiotherapy. Conclusion: Our study reveals that tumor AEP/EIF4A1/PGE2 feedback loop modulates neuron senescence upon radiotherapy. Targeting AEP/PGE2 might be a new strategy to increase radiotherapy sensitivity.
