Cimetidine promotes STUB1-mediated degradation of tumoral FOXP3 by activating PI3K-Akt pathway in gastric cancer.
Cimetidine promotes STUB1-mediated degradation of tumoral FOXP3 by activating PI3K-Akt pathway in gastric cancer.
复制标题
西咪替丁通过激活胃癌中的 PI3K-Akt 通路促进 STUB1 介导的肿瘤 FOXP3 降解
DOI：
10.21037/atm-20-6070
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发表时间：
2020-10
影响因子：
--
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Zhang L;Li Q;Xu J;Sun G;Xu Z
背景既往研究已证实西咪替丁具有抗肿瘤作用，但其治疗靶点和机制尚不完全清楚。我们之前报道了内源性FOXP3在胃癌（GC）中的促肿瘤作用，但西咪替丁是否通过靶向FOXP3发挥抗肿瘤作用仍不清楚。方法采用一系列实验检测西咪替丁对GC细胞恶性行为和内源性FOXP3表达的影响。研究了西咪替丁对连接酶E3-STUB1的作用以及STUB1对FOXP3水平的作用，并探讨了这些过程中涉及的信号通路。结果西咪替丁抑制GC细胞的恶性行为，并导致FOXP3泛素化/降解。此外，西咪替丁促进STUB1表达，STUB1敲除挽救了西咪替丁处理的GC细胞中FOXP3的下降，并降低了西咪替丁对GC细胞的周转作用，但对未处理的细胞影响甚微。免疫沉淀 (IP) 测定证实了西咪替丁处理的 GC 细胞中 STUB1-FOXP3 复合物的形成。此外，西咪替丁通过激活PI3K/Akt通路促进STUB1的表达，而抑制PI3K/Akt通路则通过抑制STUB1的上调来挽救FOXP3的下降。结论 西咪替丁通过激活 PI3K/Akt 通路促进 STUB1 介导的内源 FOXP3 泛素化/降解，从而抑制 GC 的发生。
Background Previous studies have confirmed the antitumor effects of cimetidine, while the therapeutic targets and the mechanisms are not yet fully understood. We previously reported the protumoral role of endogenous FOXP3 in gastric cancer (GC), but whether cimetidine plays an antitumor role by targeting FOXP3 is still unknown. Methods A series of assays were used to examine the role of cimetidine on the malignant behaviors and the expression of endogenous FOXP3 in GC cells. The role of cimetidine on ligase E3-STUB1and the role of STUB1 on FOXP3 level were examined, with the signaling pathway involved in these processes also being explored. Results Cimetidine inhibited the malignant behaviors of GC cells, and led to the ubiquitination/degradation of FOXP3. Moreover, cimetidine promoted STUB1 expression, STUB1 knockdown rescued the decline of FOXP3 in cimetidine-treated GC cells, and reduced the turnover effect of cimetidine on GC cells, but had minimal effect in untreated cells. Immunoprecipitation (IP) assay confirmed the formation of the STUB1-FOXP3 complex in cimetidine-treated GC cells. Furthermore, Cimetidine promoted STUB1 expression by activating PI3K/Akt pathway, and the inhibition of PI3K/Akt pathway rescued the decline of FOXP3 by suppressing the upregulation of STUB1. Conclusions Cimetidine suppressed GC development by promoting STUB1-mediated ubiquitination/degradation of endogenous FOXP3 through the activation of the PI3K/Akt pathway.
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影响因子：
45.3
作者：
DEXEUS, FH;LOGOTHETIS, CJ;DOZIER, N
通讯作者：
DOZIER, N
影响因子：
3.1
作者：
Rajendra, S;Mulcahy, H;Kumar, P
通讯作者：
Kumar, P
影响因子：
3.3
作者：
KUMAR, A;CLEVELAND, RP
通讯作者：
CLEVELAND, RP
影响因子：
45.3
作者：
MORTON, RF;CREAGAN, ET;CHANG, M
通讯作者：
CHANG, M
影响因子：
2.2
作者：
Reynolds, JL;Akhter, J;Morris, DL
通讯作者：
Morris, DL