Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation

Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we d...

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Bibliographic Details
Published in:Cell death and differentiation 2023-03, Vol.30 (3), p.809-824
Main Authors: Sun, Lili, Yao, Chen, Li, Xiaojiao, Wang, Yuxing, Wang, Ru, Wang, Molin, Liu, Qiao, Montell, Denise J., Shao, Changshun, Gong, Yaoqin, Sun, Gongping
Format: Article
Language:English
Subjects:
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Angiogenesis
Animals
Apoptosis
Apoptosis - physiology
Biochemistry
Biomedical and Life Sciences
Caspase
Caspases
Cell Biology
Cell Cycle Analysis
Cell Death Reversal
Cell migration
Female
Humans
Life Sciences
Malignancy
Mammalian cells
Mammals
MAP kinase
Metastases
Metastasis
Ovarian cancer
Ovarian Neoplasms
p38 Mitogen-Activated Protein Kinases
Paclitaxel
Stem Cells
Tumors
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Summary:Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we developed a reporter system, mCasExpress, to track mammalian cells that survive executioner caspase activation. We demonstrate that anastatic ovarian cancer cells acquire enhanced migration following their transient exposure to apoptotic stimulus TRAIL or Paclitaxel. Moreover, anastatic cancer cells secrete more pro-angiogenic factors that enable tumor angiogenesis, growth and metastasis. Mechanistically, we demonstrate that activation of p38 MAPK, which occurs in a caspase-dependent manner in response to apoptotic stress to promote anastasis, persists at a higher level in anastatic cancer cells even after removal of apoptotic stimuli. Importantly, p38 is essential for the elevated migratory and angiogenic capacity in the anastatic cells. Our work unveils anastasis as a potential driver of tumor angiogenesis and metastasis.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-022-01081-1