Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells.
Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells.
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DOI：
10.1158/0008-5472.can-07-6601
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Minna JD
中科院分区：
文献类型：
--
作者：
Castro-Rivera E;Ran S;Brekken RA;Minna JD
信号素3B（SEMA3B）位于3p21.3，是信号素家族中一种分泌型成员，在轴突导向中起重要作用。SEMA3B在肺癌和乳腺癌中发生等位基因缺失和表达缺失，并可作为一种肿瘤抑制因子发挥作用。此前我们发现，SEMA3B通过重新表达或作为可溶性配体应用时可诱导肿瘤细胞凋亡。SEMA3B诱导的凋亡部分是通过阻断肿瘤细胞中血管内皮生长因子的自分泌活性来介导的。在当前研究中，用皮摩尔浓度的可溶性SEMA3B处理肺癌和乳腺癌细胞可抑制其生长，诱导凋亡，并与Akt磷酸化降低、细胞色素c释放增加和半胱天冬酶 - 3裂解以及包括糖原合成酶激酶 - 3β、FKHR和MDM - 2在内的几种促凋亡蛋白的磷酸化增加有关。对SEMA3B有抗性的肺癌和乳腺癌细胞系未显示出这些信号变化，并且一种肿瘤来源的错义SEMA3B突变体在这方面无活性，这体现了特异性。通过表达一种组成型活性Akt突变体可阻断SEMA3B介导的癌细胞增殖抑制和凋亡诱导，并且这与神经毡蛋白 - 1（Np - 1）在肿瘤细胞中的表达有关。对SEMA3B不敏感的Np - 1阴性肿瘤细胞在强制表达Np - 1后对SEMA3B获得敏感性，而对SEMA3B敏感的Np - 1阳性肿瘤细胞在通过小干扰RNA敲低Np - 1后对SEMA3B失去敏感性。我们得出结论，SEMA3B是一种潜在的肿瘤抑制因子，它通过使Akt信号通路失活，经由Np - 1受体诱导SEMA3B失活的肿瘤细胞凋亡。
Semaphorin 3B (SEMA3B), located at 3p21.3, is a secreted member of the semaphorin family important in axonal guidance. SEMA3B undergoes allele and expression loss in lung and breast cancer and can function as a tumor suppressor. Previously, we found that SEMA3B induces apoptosis in tumor cells either by reexpression or when applied as a soluble ligand. SEMA3B-induced apoptosis was mediated, in part, by blocking vascular endothelial growth factor autocrine activity in tumor cells. In the current study, treatment of lung and breast cancer cells with picomolar concentrations of soluble SEMA3B inhibited their growth; induced apoptosis; and was associated with decreased Akt phosphorylation, increase in cytochrome c release and caspase-3 cleavage, as well as increased phosphorylation of several proapoptotic proteins, including glycogen synthase kinase-3β, FKHR, and MDM-2. Lung and breast cancer lines resistant to SEMA3B did not showthese signaling changes and a tumor-derived missense SEMA3B mutant was inactive in this regard, providing specificity. SEMA3B-mediated inhibition of proliferation and induction of apoptosis in cancer cells were blocked by expressing a constitutively active Akt mutant and are linked to tumor cell expression of neuropilin-1 (Np-1). SEMA3B-insensitive Np-1–negative tumor cells acquired sensitivity to SEMA3B after forced expression of Np-1, whereas SEMA3B-sensitive Np-1–positive tumor cells lost sensitivity to SEMA3B after knockdown of Np-1 by small interfering RNA. We conclude that SEMA3B is a potential tumor suppressor that induces apoptosis in SEMA3B-inactivated tumor cells through the Np-1 receptor by inactivating the Akt signaling pathway.