Castro-Rivera Emely, Ran Sophia, Brekken Rolf A, Minna John D
Departments of Internal Medicine, Hamon Center for Therapeutic Oncology Research-Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Cancer Res. 2008 Oct 15;68(20):8295-303. doi: 10.1158/0008-5472.CAN-07-6601.
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-3beta, FKHR, and MDM-2. Lung and breast cancer lines resistant to SEMA3B did not show these 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. CA118384
信号素3B（SEMA3B）位于3p21.3，是信号素家族的一个分泌成员，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，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的血管内皮生长因子自分泌活性介导的。在本研究中，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裂解增加以及几种促凋亡蛋白（包括糖原合酶激酶-3β、FKHR和MDM-2）的磷酸化增加有关。对SEMA3B耐药的肺癌和乳腺癌细胞系未显示这些信号变化，并且肿瘤来源的错义SEMA3B突变体在这方面无活性，具有特异性。SEMA3B介导的癌细胞增殖抑制和凋亡诱导被组成型活性Akt突变体的表达所阻断，并且与神经纤毛蛋白-1（Np-1）的肿瘤细胞表达有关。对SEMA3B不敏感的Np-1阴性肿瘤细胞在强制表达Np-1后获得了对SEMA3B的敏感性，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后失去了对SEMA3B的敏感性。我们得出结论：SEMA3B是一种潜在的肿瘤抑制因子，通过使Akt信号通路失活，通过Np-1受体在SEMA3B失活的肿瘤细胞中诱导凋亡。CA118384
