Targeting constitutively activated β1 integrins inhibits prostate cancer metastasis.
Targeting constitutively activated β1 integrins inhibits prostate cancer metastasis.
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DOI：
10.1158/1541-7786.mcr-12-0551
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Lin SH
中科院分区：
文献类型：
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作者：
Lee YC;Jin JK;Cheng CJ;Huang CF;Song JH;Huang M;Brown WS;Zhang S;Yu-Lee LY;Yeh ET;McIntyre BW;Logothetis CJ;Gallick GE;Lin SH
播散性前列腺癌 (PCa) 细胞必须在循环中存活才能发生转移。这些细胞的生存机制尚不清楚。通过人体组织的免疫组织化学，我们发现原发性前列腺癌和淋巴结转移的前列腺癌细胞中β1整合素和整合素诱导的FAK自磷酸化（pFAK-Y397）水平升高，表明β1整合素激活发生在前列腺癌的转移过程中。构象敏感抗体 9EG7 用于检查 β1 整合素激活。我们发现β1整合素在高转移性PC3和PC3-mm2细胞中被组成性激活，而在低转移性LNCaP和C4-2B4细胞中激活较少。 PCa 细胞中 β1 整合素激活的增加以及失巢凋亡抵抗与体内转移潜力相关。 β1 整合素的敲低消除了 PC3-mm2 细胞中的失巢凋亡抵抗。与 β1 整合素激活一致，PC3-mm2 细胞强烈粘附于 I 型胶原和纤连蛋白，这一过程被 β1 整合素中和抗体 mAb 33B6 抑制。 mAb 33B6 还抑制 β1 整合素下游效应器、粘着斑激酶 (FAK) 和 AKT 的磷酸化，导致 PC3-mm2 细胞凋亡增加 3 倍。 mAb 33B6 的全身递送抑制了前列腺内注射后 PC3-mm2 从前列腺到远处淋巴结的自发转移，并抑制了心脏内注射后 PC3-mm2 向多个器官的转移。因此，组成型激活的 β1 整合素在循环中 PC3-mm2 细胞的存活中发挥作用，并且是预防转移的潜在靶点。
Disseminated prostate cancer (PCa) cells must survive in circulation for metastasis to occur. Mechanisms by which these cells survive are not well understood. By immunohistochemistry of human tissues, we found that levels of β1 integrins and integrin-induced autophosphorylation of FAK (pFAK-Y397) are increased in PCa cells in primary PCa and lymph node metastases, suggesting that β1 integrin activation occurs in metastatic progression of PCa. A conformation-sensitive antibody, 9EG7, was used to examine β1 integrin activation. We found that β1 integrins are constitutively activated in highly metastatic PC3 and PC3-mm2 cells, with less activation in low metastatic LNCaP and C4-2B4 cells. Increased β1 integrin activation as well as the anoikis resistance in PCa cells correlated with metastatic potential in vivo. Knockdown of β1 integrin abrogated anoikis resistance in PC3-mm2 cells. In agreement with β1 integrin activation, PC3-mm2 cells strongly adhered to type I collagen and fibronectin, a process inhibited by the β1 integrin neutralizing antibody mAb 33B6. mAb 33B6 also inhibited the phosphorylation of β1 integrin downstream effectors, focal adhesion kinase (FAK) and AKT, leading to a 3-fold increase in PC3-mm2 apoptosis. Systemic delivery of mAb 33B6 suppressed spontaneous metastasis of PC3-mm2 from the prostate to distant lymph nodes following intra-prostatic injection and suppressed metastasis of PC3-mm2 to multiple organs following intra-cardiac injection. Thus, constitutively activated β1 integrins play a role in survival of PC3-mm2 cells in circulation and represent a potential target for metastasis prevention.