Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion.
Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion.
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DOI：
10.1371/journal.pone.0026552
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Howe AK
中科院分区：
文献类型：
--
作者：
McKenzie AJ;Campbell SL;Howe AK
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤，部分原因在于其临床隐匿性转移。因此，了解控制 EOC 传播和侵袭的机制可能为抗转移治疗提供新靶点或检测转移性疾病的新方法。 EOC 中 cAMP 依赖性蛋白激酶 (PKA) 常常失调。此外，PKA 活性和 A 激酶锚定蛋白 (AKAP) 的亚细胞定位是细胞骨架动力学和细胞迁移的重要调节因子。因此，我们试图研究 PKA 和 AKAP 功能在 EOC 细胞迁移和侵袭中的作用。使用质膜导向的 PKA 生物传感器 pmAKAR3 和改进的迁移/入侵测定，我们发现 PKA 在迁移 SKOV-3 EOC 细胞的前缘被激活，并且抑制 PKA 活性会阻止 SKOV-3 细胞迁移。此外，我们发现，虽然这些细胞前缘内的 PKA 活性是通过 II 型调节 PKA 亚基 (RII) 的锚定来介导的，但抑制 RI 或 RII PKA 亚基的锚定会阻止细胞迁移。重要的是，我们还首次表明，在入侵三维细胞外基质期间，SKOV-3 细胞前缘的 PKA 活性上调，并且如迁移所示，抑制 PKA 活性或 AKAP 介导的 PKA 锚定会阻止基质入侵。这些数据首次证明癌细胞对细胞外基质的侵袭会引起侵袭前缘内 PKA 的激活，并且 PKA 活性和锚定都是基质侵袭所必需的。这些观察结果表明 PKA 和 AKAP 活性在 EOC 转移中发挥作用。
Epithelial ovarian cancer (EOC) is the deadliest of the gynecological malignancies, due in part to its clinically occult metastasis. Therefore, understanding the mechanisms governing EOC dissemination and invasion may provide new targets for antimetastatic therapies or new methods for detection of metastatic disease. The cAMP-dependent protein kinase (PKA) is often dysregulated in EOC. Furthermore, PKA activity and subcellular localization by A-kinase anchoring proteins (AKAPs) are important regulators of cytoskeletal dynamics and cell migration. Thus, we sought to study the role of PKA and AKAP function in both EOC cell migration and invasion. Using the plasma membrane-directed PKA biosensor, pmAKAR3, and an improved migration/invasion assay, we show that PKA is activated at the leading edge of migrating SKOV-3 EOC cells, and that inhibition of PKA activity blocks SKOV-3 cell migration. Furthermore, we show that while the PKA activity within the leading edge of these cells is mediated by anchoring of type-II regulatory PKA subunits (RII), inhibition of anchoring of either RI or RII PKA subunits blocks cell migration. Importantly, we also show – for the first time – that PKA activity is up-regulated at the leading edge of SKOV-3 cells during invasion of a three-dimensional extracellular matrix and, as seen for migration, inhibition of either PKA activity or AKAP-mediated PKA anchoring blocks matrix invasion. These data are the first to demonstrate that the invasion of extracellular matrix by cancer cells elicits activation of PKA within the invasive leading edge and that both PKA activity and anchoring are required for matrix invasion. These observations suggest a role for PKA and AKAP activity in EOC metastasis.
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