DNA损伤
胰腺癌
癌症研究
癌症
第1周
化学
DNA
生物
内科学
医学
遗传学
细胞周期
细胞周期蛋白依赖激酶1
作者
Shruti Lal,Richard A. Burkhart,Neil Beeharry,Vikram Bhattacharjee,Eric Londin,Joseph A. Cozzitorto,Carmella Romeo,Masaya Jimbo,Zoë A. Norris,Charles J. Yeo,Janet A. Sawicki,Jordan M. Winter,Isidore Rigoutsos,Tim J. Yen,Jonathan R. Brody
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2014-02-15
卷期号:74 (4): 1128-1140
被引量:95
标识
DOI:10.1158/0008-5472.can-13-1915
摘要
Abstract HuR (ELAV1), an RNA-binding protein abundant in cancer cells, primarily resides in the nucleus, but under specific stress (e.g., gemcitabine), HuR translocates to the cytoplasm in which it tightly modulates the expression of mRNA survival cargo. Here, we demonstrate for the first time that stressing pancreatic ductal adenocarcinoma (PDA) cells by treatment with DNA-damaging anticancer agents (mitomycin C, oxaliplatin, cisplatin, carboplatin, and a PARP inhibitor) results in HuR's translocation from the nucleus to the cytoplasm. Importantly, silencing HuR in PDA cells sensitized the cells to these agents, whereas overexpressing HuR caused resistance. HuR's role in the efficacy of DNA-damaging agents in PDA cells was, in part, attributed to the acute upregulation of WEE1 by HuR. WEE1, a mitotic inhibitor kinase, regulates the DNA damage repair pathway, and therapeutic inhibition of WEE1 in combination with chemotherapy is currently in early phase trials for the treatment of cancer. We validate WEE1 as a HuR target in vitro and in vivo by demonstrating (i) direct binding of HuR to WEE1′s mRNA (a discrete 56-bp region residing in the 3′ untranslated region) and (ii) HuR siRNA silencing and overexpression directly affects the protein levels of WEE1, especially after DNA damage. HuR's positive regulation of WEE1 increases γ-H2AX levels, induces Cdk1 phosphorylation, and promotes cell-cycle arrest at the G2–M transition. We describe a novel mechanism that PDA cells use to protect against DNA damage in which HuR posttranscriptionally regulates the expression and downstream function of WEE1 upon exposure to DNA-damaging agents. Cancer Res; 74(4); 1128–40. ©2014 AACR.
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