癌症研究
NF-κB
信号转导
细胞凋亡
转移
NFKB1型
化学
细胞生物学
医学
生物
癌症
内科学
转录因子
生物化学
基因
作者
Chenchen Zhu,Pei Liu,Chuan‐Yuan Li,Yuli Zhang,Jiang Yin,Linlin Hou,Guopei Zheng,Xinjian Liu
标识
DOI:10.1002/advs.202205835
摘要
Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy-induced cancer recurrence and metastasis. It is revealed that a small subpopulation of "near-death cells" (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)-dependent nonclassical NF-κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF-κB signaling pathway to promote chemotherapy-induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy-induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy.
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