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

作　　者：Liu, Xinjian Li, Fang Huang, Qian Zhang, Zhengxiang Zhou, Ling Deng, Yu Zhou, Min Fleenor, Donald E. Wang, He Kastan, Michael B. Li, Chuan-Yuan[1,5,7] 

机构地区：[1]Duke Univ, Med Ctr, Dept Dermatol, Durham, NC 27710 USA [2]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Canc Ctr, Shanghai 201620, Peoples R China [3]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Branch Hosp, Dept Surg, Shanghai 200081, Peoples R China [4]Shanghai Jiao Tong Univ, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes, Shanghai 200032, Peoples R China [5]Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA [6]Sichuan Univ, West China Univ Hosp 2, Chengdu 610041, Peoples R China [7]Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27710 USA

出　　处：《Cell Research》2017年第6期764-783,共20页细胞研究（英文版）

摘　　要：DNA double-strand breaks （DSBs） are traditionally associated with cancer through their abilities to cause chro- mosomal 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 mech- anism, 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- KB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the sternness 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.

关 键 词：sublethal caspase activation spontaneous DNA double-strand breaks DNA damage response ATM activation cancer stem cells 

分 类 号：Q691[生物学—生物物理学] Q279