The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer
The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer
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DOI：
10.1002/ijc.32607
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发表时间：
2019-08-16
影响因子：
6.4
通讯作者：
Persson, Jenny L.
中科院分区：
文献类型：
--
作者：
Larsson, Per;Khaja, Azharuddin Sajid Syed;Persson, Jenny L.
目前，不存在用于治疗转移性前列腺癌（PCa）的有效靶向治疗剂。鉴于基质金属蛋白酶9（MMP 9）及其相关的血管内皮生长因子（VEGF）在去势抵抗条件下对肿瘤血管形成和侵袭至关重要，因此确定雄激素受体（AR）和MMP 9之间的功能关联和相互作用以及它们在PCa细胞中相关的关键存活和侵袭途径是非常重要的。在此，我们发现在原发性和转移性PCa组织中MMP 9和AR蛋白表达之间存在显著相关性，并且MMP 9高水平表达与不良预后相关的趋势。我们证明了AR的组成性激活增加了MMP 9和VEGF/VEGF受体的表达。我们进一步表明，AR通过PIP 5 K1 α/AKT对MMP 9/VEGF信号转导轴发挥作用。我们发现MMP 9通过形成蛋白质-蛋白质复合物与PIP 5 K1 α发生物理相互作用。此外，MMP 9的表达增加增强AR激活其靶基因cyclin A1的能力。AR/PIP 5 K1 α/AKT/MMP 9/VEGF信号传导轴的顺序激活升高有助于增加转移性肿瘤的侵袭性和生长。相反，用PIP 5 K1 α抑制剂处理显著抑制表达组成性活化AR的PCa细胞的侵袭性，这与该抑制剂对AR/MMP 9/VEGF途径的抑制作用一致。我们的研究结果表明，AR和MMP 9相关的网络蛋白可以有效地通过使用PIP 5 K1 α抑制剂阻断PIP 5 K1 α/AKT通路在转移性PCa。
Currently, no effective targeted therapeutics exists for treatment of metastatic prostate cancer (PCa). Given that matrix metalloproteinases 9 (MMP9) and its associated vascular endothelial growth factor (VEGF) are critical for tumor vascularization and invasion under castration-resistant condition, it is therefore of great importance to define the functional association and interplay between androgen receptor (AR) and MMP9 and their associated key survival and invasion pathways in PCa cells. Here, we found that there was a significant correlation between MMP9 and AR protein expression in primary and metastatic PCa tissues, and a trend that high level of MMP9 expression was associated with poor prognosis. We demonstrated that constitutive activation of AR increased expression of MMP9 and VEGF/VEGF receptors. We further showed that AR exerts its effect on MMP9/VEGF signaling axis through PIP5K1 alpha/AKT. We showed that MMP9 physically interacted with PIP5K1 alpha via formation of protein-protein complexes. Furthermore, elevated expression of MMP9 enhanced ability of AR to activate its target gene cyclin A1. The elevated sequential activation of AR/PIP5K1 alpha/AKT/MMP9/VEGF signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1 alpha inhibitor significantly suppressed invasiveness of PCa cells expressing constitutively activated AR, this was coincident with its inhibitory effect of this inhibitor on AR/MMP9/VEGF pathways. Our results suggest that AR and MMP9-associated network proteins may be effectively targeted by blocking PIP5K1 alpha/AKT pathways using PIP5K1 alpha inhibitor in metastatic PCa.