Increased protein kinase C delta in mammary tumor cells: relationship to transformtion and metastatic progression.
Increased protein kinase C delta in mammary tumor cells: relationship to transformtion and metastatic progression.
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发表时间：
1999
期刊：
影响因子：
8
通讯作者：
S. Kiley;K. Clark;S. Duddy;D. Welch;S. Jaken
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文献类型：
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作者：
S. Kiley;K. Clark;S. Duddy;D. Welch;S. Jaken
目前对乳腺癌发生中肿瘤促进/进展的分子机制知之甚少。已知蛋白激酶C（PKC）活性增加可促进几种组织中的肿瘤形成;然而，其在乳腺癌发生中的作用尚不清楚。为了确定单个PKC是否可以选择性地调节乳腺肿瘤细胞的特性，我们比较了具有低、中、高转移潜能的乳腺肿瘤细胞系中的PKC同工酶水平。所有三种细胞系均表达α、δ、β和zeta PKC;然而，在高转移性细胞中PKC δ水平相对增加。为了确定增加的PKC δ是否有助于促进/进展，我们在低和中度转移细胞系中过表达PKC δ。PKC δ过表达对贴壁细胞的生长没有显著影响，但显著增加了锚定非依赖性生长。相反，表达PKC δ的调节结构域（RD δ），一个假定的PKC δ抑制片段，抑制锚定非依赖性生长。RD δ作为PKC δ抑制剂的有效性通过显示RD δ选择性干扰PKC δ亚细胞定位并显著干扰PKC细胞骨架底物内收蛋白的磷酸化来证明。细胞骨架底物蛋白（如内收蛋白）的PKC依赖性磷酸化提供了PKC δ活性增加与细胞骨架依赖性过程（如迁移和附着，这两个过程与转移潜能相关）中表型变化之间的机制联系。表达PKC δ和RD δ作为功能结构的获得和丧失的相互生长效应分别提供了强有力的证据，证明PKC δ调节这些乳腺肿瘤细胞中对锚定非依赖性生长重要的过程。
Relatively little is known about the molecular mechanisms of tumor promotion/progression in mammary carcinogenesis. Increased protein kinase C (PKC) activity is known to promote tumor formation in several tissues; however, its role in mammary carcinogenesis is not yet known. To determine if individual PKCs may selectively regulate properties of mammary tumor cells, we compared PKC isozyme levels in mammary tumor cell lines with low, moderate and high metastatic potential. All three cell lines expressed alpha, delta, epsilon and zeta PKCs; however, PKC delta levels were relatively increased in the highly metastatic cells. To determine if increased PKC delta could contribute to promotion/progression, we overexpressed PKC delta in the low and moderately metastatic cell lines. PKC delta overexpression had no significant effect on growth of adherent cells, but significantly increased anchorage-independent growth. Conversely, expressing the regulatory domain of PKC delta (RD delta), a putative PKC delta inhibitory fragment, inhibited anchorage-independent growth. The efficacy of RD delta as a PKC delta inhibitor was demonstrated by showing that RD delta selectively interfered with PKC delta subcellular location and significantly interfered with phosphorylation of the PKC cytoskeletal substrate, adducin. PKC-dependent phosphorylation of cytoskeletal substrate proteins, such as adducin, provides a mechanistic link between increased PKC delta activity and phenotypic changes in cytoskeletal-dependent processes such as migration and attachment, two processes that are relevant to metastatic potential. The reciprocal growth effects of expressing PKC delta and RD delta as gain and loss of function constructs, respectively, provide strong evidence that PKC delta regulates processes important for anchorage-independent growth in these mammary tumor cells.