The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs.
The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs.
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DOI：
10.3390/biom11121758
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发表时间：
2021-11-24
期刊：
影响因子：
5.5
通讯作者：
Petrella A
中科院分区：
文献类型：
--
作者：
Belvedere R;Morretta E;Novizio N;Morello S;Bruno O;Brullo C;Petrella A
吡唑基脲Gege 3分子在肿瘤竞赛中表现出有趣的抗血管生成作用。在这里，我们已经研究了这种化合物的作用，作为干扰内皮细胞激活响应膜联蛋白A1（ANXA 1），已知参与促进肿瘤进展的旁分泌效应。已经在胰腺癌（PC）细胞通过微泡（EV）分泌的细胞外环境中分析了ANXA 1。特别地，Gege 3能够显著地防止Ac 2 -26（ANXA 1模拟肽）和PC衍生的EV对内皮细胞运动性、血管生成和钙释放的影响。此外，该化合物还抑制ANXA 1向质膜的移位，否则由相同的ANXA 1依赖性细胞外刺激诱导。此外，这些作用是通过间接抑制蛋白激酶Cα（PKCα）介导的，PKC α通常促进ANXA 1在丝氨酸27上的磷酸化。事实上，通过减去细胞内钙水平，PKCα触发的途径受到强烈抑制，导致ANXA 1在质膜上定位的以下障碍，如共聚焦和细胞荧光分析所示。因此，Gege 3似乎是一个有吸引力的分子，能够阻止肿瘤微环境中衍生ANXA 1的PC细胞的旁分泌效应。
The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells. Particularly, Gege3 has been able to notably prevent the effects of Ac2-26, the ANXA1 mimetic peptide, and of PC-derived EVs on endothelial cells motility, angiogenesis, and calcium release. Furthermore, this compound also inhibited the translocation of ANXA1 to the plasma membrane, otherwise induced by the same ANXA1-dependent extracellular stimuli. Moreover, these effects have been mediated by the indirect inhibition of protein kinase Cα (PKCα), which generally promotes the phosphorylation of ANXA1 on serine 27. Indeed, by the subtraction of intracellular calcium levels, the pathway triggered by PKCα underwent a strong inhibition leading to the following impediment to the ANXA1 localization at the plasma membrane, as revealed by confocal and cytofluorimetry analysis. Thus, Gege3 appeared an attractive molecule able to prevent the paracrine effects of PC cells deriving ANXA1 in the tumor microenvironment.
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DOI：
10.1111/febs.16043
发表时间：
2021-11
期刊：
The FEBS journal
影响因子：
--
作者：
Pessolano E;Belvedere R;Novizio N;Filippelli A;Perretti M;Whiteford J;Petrella A
通讯作者：
Petrella A
影响因子：
4.6
作者：
Belvedere R;Bizzarro V;Forte G;Dal Piaz F;Parente L;Petrella A
通讯作者：
Petrella A
影响因子：
11.8
作者：
Eden ER;Sanchez-Heras E;Tsapara A;Sobota A;Levine TP;Futter CE
通讯作者：
Futter CE
影响因子：
6
作者：
Novizio N;Belvedere R;Pessolano E;Tosco A;Porta A;Perretti M;Campiglia P;Filippelli A;Petrella A
通讯作者：
Petrella A
癌症抗血管生成治疗的当前挑战和纳米治疗的前景。
影响因子：
12.4
作者：
Abdalla AME;Xiao L;Ullah MW;Yu M;Ouyang C;Yang G
通讯作者：
Yang G