PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas.
PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas.
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DOI：
10.1002/ijc.31859
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发表时间：
2019-02-15
影响因子：
6.4
通讯作者：
Bastiaens PIH
中科院分区：
文献类型：
--
作者：
Klein CH;Truxius DC;Vogel HA;Harizanova J;Murarka S;Martín-Gago P;Bastiaens PIH
Ras蛋白，尤其是KRas，是人类癌症中普遍存在的致癌基因。质膜定位和KRas的信号传导是由烯丙基结合蛋白PDEδ调节的。最近，我们报道了PDEδ抑制对KRas依赖性人胰腺导管腺癌细胞系的特异性抗增殖作用。在这里，我们研究了具有或不具有致癌KRas突变的人结直肠癌（CRC）细胞系对PDEδ增溶活性的增殖依赖性。我们的研究结果表明，基因和药理学干扰PDEδ特异性抑制含有致癌KRas突变的结直肠癌细胞系的增殖和存活，而KRas癌基因被去除的等基因细胞系，或具有致癌BRaf突变或EGFR过表达的细胞系不依赖于PDEδ。因此，药理学抑制PDEδ可能是靶向携带结直肠癌的致癌KRas的新途径。有什么新鲜事吗?致癌性KRas突变存在于约45%的结直肠癌（crc）中，与预后不良相关。虽然KRas是一个有吸引力的治疗靶点，但它一再避开小分子抑制剂。在这里，作者选择靶向PDEδ，这是一种调节KRas质膜定位的烯丙基结合蛋白。在人类结直肠癌细胞的实验中，PDEδ抑制抑制了KRas突变细胞的增殖和存活，而对野生型KRas细胞没有影响，这为携带致癌KRas的结直肠癌提供了新的治疗机会。此外，在结直肠癌细胞组中，PDEδ蛋白表达与致癌KRas活性相关，表明PDEδ蛋白水平的测定可能与结直肠癌患者的预后相关。
Ras proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl‐binding protein PDEδ. Recently, we have reported the specific anti‐proliferative effects of PDEδ inhibition in KRas‐dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC. What's new? Oncogenic KRas mutations are present in about 45% of colorectal cancers (CRCs), where they are associated with poor prognosis. While KRas is an appealing therapeutic target, it has repeatedly eluded small‐molecule inhibitors. Here, the authors chose instead to target PDEδ, a prenyl‐binding protein that regulates the plasma membrane localization of KRas. In experiments in human colorectal cancer cells, PDEδ inhibition limited proliferation and survival in cells harboring KRas mutations, with no effect on wild‐type KRas cells, providing a new therapeutiv opportunity for CRC harbouring oncogenic KRas. In addition, PDEδ protein expression was correlated with oncogenic KRas activity within the CRC cell panel, suggesting that PDEδ protein‐level determination may be of prognostic relevance for CRC patients.
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影响因子：
14.8
作者：
Ismail, Shehab A.;Chen, Yong-Xiang;Wittinghofer, Alfred
通讯作者：
Wittinghofer, Alfred
影响因子：
51.1
作者：
Moroni, M;Veronese, S;Bardelli, A
通讯作者：
Bardelli, A
影响因子：
64.8
作者：
Zimmermann, Gunther;Papke, Bjoern;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
影响因子：
11.4
作者：
MARAIS, R;LIGHT, Y;MARSHALL, CJ
通讯作者：
MARSHALL, CJ
影响因子：
2.9
作者：
Zembruski, Nadine C. L.;Stache, Vanessa;Weiss, Johanna
通讯作者：
Weiss, Johanna