title: eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation.
abstract: Pancreatic cancer is a devastating disease characterized by treatment resistance and high recurrence rate. Repopulation of surviving tumor cells undergoing radiotherapy is one of the most common reasons for recurrence. Our previous studies have discovered a novel mechanism for repopulation after irradiation that activation of caspase-3 in irradiated tumor cells activates PKCδ/p38 axis to transmit proliferation signals promoting repopulation of surviving tumor cells. Here we found Sox2 expression is up-regulated in irradiated pancreatic cancer cells, which played a major role in tumor cell repopulation after irradiation. Over-expression of Sox2 strongly enhanced the growth-stimulating effect of irradiated dying tumor cells on living tumor cells through a paracrine modality. Furthermore, we identified activated eIF4E, which is phosphorylated by MNK1, as a regulator of Sox2 expression after irradiation, and pharmacologic inhibition of eIF4E with CGP57380 and Ribavirin significantly weakened Sox2-mediated tumor cell repopulation. Finally, we showed the activation of caspase 3/PKCδ/p38/MNK1 signal pathway in irradiated pancreatic tumor cells. Together, we showed a novel pathway regulating Sox2 expression and Sox2 may be a promising target to reduce recurrence due to repopulation of surviving tumor cells after radiotherapy.
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, 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 201620, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Feng
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, 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 201620, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: The Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, 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 201620, China.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Yang
authors.affiliation: The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
authors.forename: Sijia
authors.initials: S
authors.lastname: He
authors.affiliation: The Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: chuan.li@duke.edu.
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 201620, China. Electronic address: Qhuang@sjtu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011836:Radiation Tolerance; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: Caspase 3; Repopulation; Sox2; X-irradiation; eIF4E