Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway.

Published online

Journal Article

BACKGROUND: Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. METHODS: Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. RESULTS: Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. CONCLUSIONS: Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Zhao, M; He, S; Luo, Y; Zhao, Y; Cheng, J; Gong, Y; Xie, J; Wang, Y; Hu, B; Tian, L; Liu, X; Li, C; Huang, Q

Published Date

  • November 9, 2019

Published In

Volume / Issue

  • 38 / 1

Start / End Page

  • 461 -

PubMed ID

  • 31706322

Pubmed Central ID

  • 31706322

Electronic International Standard Serial Number (EISSN)

  • 1756-9966

Digital Object Identifier (DOI)

  • 10.1186/s13046-019-1423-5

Language

  • eng

Conference Location

  • England