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Cancer Lett. 2016 May 28;375(1):31-38. doi: 10.1016/j.canlet.2016.02.052. Epub 2016 Mar 2.

eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation.

Author information

1
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
2
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
3
The Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
4
The Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: chuan.li@duke.edu.
5
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.

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.

KEYWORDS:

Caspase 3; Repopulation; Sox2; X-irradiation; eIF4E

PMID:
26945967
DOI:
10.1016/j.canlet.2016.02.052
[Indexed for MEDLINE]

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