Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells.
Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells.
复制标题
Telmisartan通过阻断结肠癌细胞中ProHB-EGF C末端片段的核易位来抑制细胞增殖。
DOI：
10.1371/journal.pone.0056770
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Joh T
中科院分区：
文献类型：
--
作者：
Ozeki K;Tanida S;Morimoto C;Inoue Y;Mizoshita T;Tsukamoto H;Shimura T;Kataoka H;Kamiya T;Nishiwaki E;Ishiguro H;Higashiyama S;Joh T
目前针对晚期结直肠癌的治疗靶点主要集中在表皮生长因子受体（EGFR）信号转导上，但其与化疗的叠加作用仍然有限。解整合素和金属蛋白酶（ADAM）切割前肝素结合表皮生长因子样生长因子（proHB-EGF）。可溶性HB-EGF激活EGFR。同时，proHB-EGF的羧基端片段（HB-EGF-CTF）转位到细胞内膜，通过与转录抑制因子--核早幼粒细胞白血病锌指蛋白（PLZF）结合，调节细胞增殖，从而引起其核输出。我们推测抑制HB-EGF-CTF核转位可能是防止细胞增殖的新策略。处理12-O-十四烷酰基佛波-13-乙酸酯（TPA）以活化ADAM。用Alphascreen系统筛选了9000种化合物对HB-EGF-CTF与早幼粒细胞白血病锌指（PLZF）结合的阻断作用。然后将获得的候选物用于阻断结肠癌细胞HT 29和HCT 116中HB-EGF-CTF与PLZF的结合。用生长曲线测定法研究细胞增殖。细胞内定位，HB-EGF-CTF和PLZF之间的关联，分别用免疫荧光染色，免疫沉淀和Western印迹进行评估。还研究了获得的候选物对EGFR磷酸化和对HB-EGF-CTF的核转位以及在血管紧张素II 1型受体（AT 1 R）敲低期间PLZF的输出的影响。替米沙坦和坎地沙坦被认为是潜在的候选药物。替米沙坦对TPA诱导的细胞增殖的抑制作用强于坎地沙坦。在TPA刺激期间，替米沙坦（而非坎地沙坦）阻断HB-EGF-CTF的核转位以及HB-EGF-CTF与PLZF的结合。替米沙坦和坎地沙坦均不抑制TPA诱导的EGFR磷酸化，并且在AT 1 R敲低后，替米沙坦而非坎地沙坦抑制TPA诱导的HB-EGF-CTF核转位。替米沙坦抑制HB-EGF-CTF核转位可能是一种新的抑制细胞增殖的策略。
Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.
登录
查看更多内容
影响因子：
3.8
作者：
Shimura T;Yoshida M;Fukuda S;Ebi M;Hirata Y;Mizoshita T;Tanida S;Kataoka H;Kamiya T;Higashiyama S;Joh T
通讯作者：
Joh T
影响因子：
8.2
作者：
Yoshida, T.;Yamagishi, S.;Sata, M.
通讯作者：
Sata, M.
DOI：
10.1016/j.bbrc.2007.11.015
发表时间：
2008-01-18
影响因子：
3.1
作者：
Yotsumoto, Fusanorl;Yagi, Hiroshi;Miyamoto, Shingo
通讯作者：
Miyamoto, Shingo
影响因子：
4.2
作者：
Funao, Kiyoaki;Matsuyama, Masahide;Yoshimura, Rikio
通讯作者：
Yoshimura, Rikio
影响因子：
56.9
作者：
HIGASHIYAMA, S;ABRAHAM, JA;KLAGSBRUN, M
通讯作者：
KLAGSBRUN, M