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Cell Res. 2017 Jun;27(6):764-783. doi: 10.1038/cr.2017.41. Epub 2017 Mar 24.

Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.

Author information

1
Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
2
Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China.
3
Department of Surgery, Shanghai General Branch Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200081, China.
4
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai JiaotongUniversity, Shanghai 200032, China.
5
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
6
West China Second University Hospital, Sichuan University, Chengdu 610041, China.
7
Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mechanism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF-κB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the stemness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self-inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells.

PMID:
28337983
PMCID:
PMC5518870
DOI:
10.1038/cr.2017.41
[Indexed for MEDLINE]
Free PMC Article

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