P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion
P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion
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DOI：
10.1074/jbc.m112.424770
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
--
作者：
Goc, Anna;Al-Azayzih, Ahmad;Somanath, Payaningal R.
P21激活激酶（Paks）是GTP酶的小Rho家族下游的主要效应物。在六种异构体中，Pak 1是最普遍和最具特征的成员。先前的研究表明，与其他组织相比，Pak 6主要存在于前列腺中，抑制Pak 6可抑制体内前列腺肿瘤的生长。尽管Pak 1已在正常前列腺上皮细胞和癌细胞中被鉴定，但其在前列腺癌发展中的具体作用仍不清楚。我们在这里报告说，高度侵袭性前列腺癌细胞表达的Pak 1蛋白水平显着高于非侵袭性前列腺癌细胞。此外，前列腺肿瘤组织和转移到肺的前列腺癌与正常组织相比显示出更高的Pak 1表达。有趣的是，Pak 6蛋白表达水平不随癌细胞或肿瘤的侵袭/转移潜力而改变。虽然Pak 1的抑制，而不是Pak 6，导致受损的PC 3细胞迁移，Pak 1敲除跨内皮迁移（微侵袭），肿瘤生长和肿瘤血管生成的影响是高于Pak 6敲除。最后，基因阵列数据显示，在PC 3细胞中，Pak 1或Pak 6基因表达的消融降低了基质金属蛋白酶9的表达，而TGF β的蛋白水平显著升高，特异性调节Pak 1活性或消融Pak 1基因。我们的观察结果表明，虽然在前列腺癌细胞中Pak 1和Pak 6之间存在一定程度的功能冗余，但靶向Pak 1是管理前列腺肿瘤生长、微侵袭和转移的潜在选择。
P21-activated kinases (Paks) are major effectors downstream of the small Rho family of GTPases. Among the six isoforms, Pak1 is the most ubiquitous and the best characterized member. Previous studies have shown that inhibition of Pak6, which is predominantly present in the prostate compared with other tissues, inhibits prostate tumor growth in vivo. Even though Pak1 has been identified in normal prostatic epithelial cells and cancer cells, its specific role in the development of prostate cancer remains unclear. We report here that highly invasive prostate cancer cells express significantly higher levels of Pak1 protein compared with non-invasive prostate cancer cells. Furthermore, prostate tumor tissues and prostate cancer metastasized to lungs showed a higher expression of Pak1 compared with normal tissues. Interestingly, Pak6 protein expression levels did not change with the invasive/metastatic potential of the cancer cells or tumors. Although inhibition of Pak1, and not Pak6, resulted in impaired PC3 cell migration, the effects of Pak1 knockdown on transendothelial migration (microinvasion), tumor growth, and tumor angiogenesis was higher compared with Pak6 knockdown. Finally, gene array data revealed reduced expression of matrix metalloproteinase 9 with the ablation of either Pak1 or Pak6 gene expression in PC3 cells, whereas protein levels of TGF beta was elevated significantly with specific modulation of Pak1 activity or ablation of the Pak1 gene. Our observations suggest that although some level of functional redundancy exists between Pak1 and Pak6 in prostate cancer cells, targeting Pak1 is a potential option for the management of prostate tumor growth, microinvasion, and metastasis.