Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the α-platelet-derived growth factor receptor
Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the α-platelet-derived growth factor receptor
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DOI：
10.1158/0008-5472.can-06-2593
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发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Fatatis, Alessandro
中科院分区：
文献类型：
--
作者：
Dolloff, Nathan G.;Russell, Mike R.;Fatatis, Alessandro
调节播散性前列腺癌细胞趋骨性的因素仍然是模糊的。我们报道，转移到骨骼的前列腺癌细胞对人类骨髓的反应强烈地刺激了磷脂酰肌醇3-激酶/Akt通路，而缺乏骨转移潜力的前列腺癌细胞的反应可以忽略不计。这种Akt的激活主要依赖于α-血小板衍生生长因子受体(α-PDGFR)信号，这是使用PDGFR信号的小分子抑制剂AG1296显示的。在骨髓抽吸物中发现低浓度的PDGF-AA和PDGF-BB，这并不是α-PDGFR信号高水平的原因。此外，使用α-PDGFR特异性抗体(IMC-3G3)中和PDGF结合并不能显著抑制骨髓诱导的Akt激活。然而，在刺激α-PDGFR内化的条件下孵育时，IMC-3G3的抑制作用与AG1296相当。我们认为，除了天然配体外，α-PDGFR还可被人骨髓中含有的多种可溶性因子激活，这种反式激活依赖于受体在质膜上的定位。因此，α-PDGFR的表达可能在骨骼微环境中为选定的前列腺表型提供生长优势。
The factors regulating the bone tropism of disseminated Prostate cancer cells are still vaguely defined. We report that prostate cancer cells that metastasize to the skeleton respond to human bone marrow with a robust stimulation of the phosphatidylinositol 3-kinase/Akt pathway, whereas prostate cells that lack bone-metastatic potential respond negligibly. The majority of this Akt activation is dependent on alpha-platelet-derived growth factor receptor (alpha-PDGFR) signaling, which was shown using the small-molecule inhibitor of PDGFR signaling AG1296. Low concentrations of PDGF-AA and PDGF-BB found in bone marrow aspirates, which were detected by ELISA, do not account for the high levels of alpha-PDGFR signaling. Additionally, neutralizing PDGF binding using a alpha-PDGFR-specific antibody (IMC-3G3) failed to produce a significant inhibition of bone marrow-induced Akt activation. However, the inhibitory effect of IMC-3G3 rivaled that of AG1296 when incubation was done under conditions that stimulated alpha-PDGFR internalization. We conclude that alpha-PDGFR is activated by multiple soluble factors contained within human bone marrow, in addition to its natural ligands, and this transactivation is dependent on receptor localization to the plasma membrane. Therefore, alpha-PDGFR expression may provide select prostate phenotypes with a growth advantage within the bone microenvironment.