卵巢癌
下调和上调
泛素连接酶
转移
泛素
MAPK/ERK通路
癌症研究
蛋白激酶A
化学
癌细胞
激酶
细胞生物学
生物
癌症
生物化学
基因
遗传学
作者
Xingyun Wu,Li Luo,Mao Wang,Lixia Dong,Jiawu Fan,Yan Zeng,Sijia Li,Kui Wang
标识
DOI:10.1002/advs.202416484
摘要
Abstract Cancer cells cope with oxidative stress for their proliferation and metastasis by equipping antioxidant systems, among which the antioxidant enzymes peroxiredoxins (PRDXs) play crucial roles. However, whether PRDXs exhibit nonenzymatic functions remains unclear. Here, it is shown that the 1‐cysteine PRDX (PRDX6) upregulates nicotinamide N ‐methyltransferase (NNMT) to promote the growth and metastasis of ovarian cancer cells, independently of PRDX6's enzymatic activities. Mechanistically, PRDX6 interacts with NNMT to prevent its binding to the E3 ubiquitin ligase tripartite‐motif protein 56 (TRIM56), leading to the inhibition of NNMT ubiquitination at lysine 23 and 210 and suppression of subsequent proteasomal degradation. In addition, PRDX6‐mediated NNMT upregulation activates mitogen‐activated protein kinase (MAPK) signaling, thereby promoting the growth and metastasis of ovarian cancer cells. Notably, PRDX6 overexpression is associated with higher NNMT protein levels in human ovarian cancer tissues and is predictive of poor prognosis of ovarian cancer patients. Overall, the findings illustrate a critical oncogenic mechanism of the antioxidant enzyme PRDX6 in promoting ovarian cancer progression beyond its enzymatic mechanisms.
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