Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells
Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3) in breast cancer cells
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DOI：
10.1074/jbc.274.23.16407
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发表时间：
1999-06-04
影响因子：
4.8
通讯作者：
Baxter, RC
中科院分区：
文献类型：
--
作者：
Martin, JL;Baxter, RC
胰岛素样生长因子结合蛋白-3（IG-FBP-3）抑制正常和恶性细胞的增殖并促进细胞凋亡。在MCF-10A人乳腺上皮细胞中，30 ng/ml人血浆来源的IGFBP-3抑制DNA合成至对照的70%。这种抑制似乎与IGF无关，因为IGF受体抗体和IGFBP-6都不抑制DNA合成。通过转染Ha-ras癌基因的MCF-10A细胞的恶性转化消除了IGFBP-3的抑制作用，同时IGFBP-3分泌和细胞结合分别增加约60%和300%。当使用PD 98059部分抑制丝裂原活化蛋白（MAP）激酶活化时，ras转染细胞中的IGFBP-3敏感性恢复，在10 ng/ml IGFBP-3时具有显著抑制作用。PD 98059对ras转染或亲本MCF-10A细胞的IGFBP-3分泌或细胞结合无影响。Hs 578 T，一种表达活化Ha-ras的肿瘤来源的乳腺癌细胞系，同样具有高水平的分泌和细胞相关IGFBP-3。在不存在PD 98059的情况下，通过1000 ng/ml IGFBP-S将Hs 578 T细胞的DNA合成降低至对照的70%。PD 98059增加了对IGFBP-3的敏感性，因此使用100 ng/ml IGFBP-3可达到该抑制水平。这些结果表明，MAP激酶激活致癌ras表达导致IGFBP-3的阻力，乳腺癌细胞生长失调的一个可能的因素。
Insulin-like growth factor binding protein-3 (IG-FBP-3) inhibits proliferation and promotes apoptosis in normal and malignant cells. In MCF-10A human mammary epithelial cells, 30 ng/ml human plasma-derived IGFBP-3 inhibited DNA synthesis to 70% of control. This inhibition appeared IGF-independent, since neither an IGF-receptor antibody nor IGFBP-6 inhibited DNA synthesis. Malignant transformation of MCF-10A cells by transfection with Ha-ras oncogene abolished the inhibitory effect of IGFBP-3, concomitant with an increase in IGFBP-3 secretion and cell association of approximately 60 and 300%, respectively. When mitogen-activated protein (MAP) kinase activation was partially inhibited using PD 98059, IGFBP-3 sensitivity in ras-transfected cells was restored, with a significant inhibitory effect at 10 ng/ml IGFBP-3. PD 98059 had no effect on IGFBP-3 secretion or cell association by ras-transfected or parent MCF-10A cells. Hs578T, a tumor-derived breast cancer cell line that expresses activated Ha-ras, similarly has a high level of secreted and cell-associated IGFBP-3. In the absence of PD 98059, DNA synthesis by Hs578T cells was reduced to 70% of control by 1000 ng/ml IGFBP-S. PD 98059 increased sensitivity to IGFBP-3, so that this level of inhibition was achieved with 100 ng/ml IGFBP-3. These results suggest that MAP kinase activation by oncogenic ras expression causes IGFBP-3 resistance, a possible factor in the dysregulation of breast cancer cell growth.