文章：

蛋白激酶C和其他二酰基甘油在癌症中的效应

Protein kinase C and other diacylglycerol effectors in cancer

原文发布日期：2007-04-01

DOI: 10.1038/nrc2110

类型: Review Article

开放获取: 否

要点：

1. Protein kinase C (PKC) is a family of serine/threonine kinases that regulates a diverse set of cellular processes including proliferation, apoptosis, cell survival and migration, and there is a substantial amount of evidence linking PKC to tumorigenesis. Studying PKC regulation of these processes and how misregulation might contribute to tumorigenesis is complicated by the fact that each individual PKC isozyme has a distinct role in these processes in a cell-type-dependent manner.
2. There is a limited number of instances in which mutation of PKCs in humans is linked to a cancer phenotype; however, altered levels of PKC isoforms can be found in many types of human cancers. In many cases, altered expression of PKC can also be linked to disease progression.
3. PKCs were originally thought to be pro-mitogenic kinases, but this effect seems to be PKC-isozyme-dependent and cell-type-dependent, as many PKCs can also inhibit cell-cycle progression. Several PKCs have been shown to be anti-proliferative in various cell types, generally through upregulation of cell-cycle inhibitors.
4. PKCε promotes cell survival in many cell types through increased activation of the Akt pathway and upregulation of pro-survival factors. Furthermore, PKCε overexpression has been linked to chemotherapeutic resistance in various cell types.
5. PKCδ is generally considered a growth inhibitory or pro-apoptotic PKC, and many types of apoptotic stimuli can induce PKCδ translocation to mitochondria, leading to cytochrome c release, caspase-3 cleavage and generation of a constitutively active PKCδ catalytic fragment that is important for phosphorylation of nuclear PKC substrates. Activation of PKCδ can also trigger the autocrine secretion of death factors and kill cells through the activation of the extrinsic apoptotic pathway.
6. Several PKCs have been implicated in invasion and metastasis of cancer cells; however, knowledge of the molecular mechanisms through which PKC might contribute to these processes is still vague.
7. Emerging evidence indicates that PKC, specifically PKCβII, might be an important mediator of vascular endothelial growth factor (VEGF)-induced angiogenesis and have a role in VEGF-induced endothelial-cell proliferation.
8. Several other classes of proteins can be activated by phorbol esters or DAG, including protein kinase D, Ras guanyl nucleotide-releasing proteins, chimaerins, diacylglycerol kinases and Munc13s. Several of these proteins have also been implicated in cancer progression.

要点翻译：

1. 蛋白激酶C（PKC）是一个丝氨酸/苏氨酸激酶家族，调控包括增殖、凋亡、细胞存活与迁移在内的多种细胞过程。大量证据表明PKC与肿瘤发生密切相关。由于每种PKC同工酶在这些过程中均以细胞类型依赖的方式发挥独特作用，使得研究PKC对这些过程的调控及其失调如何促进肿瘤发生变得复杂。
2. 人类PKC突变与癌症表型直接关联的案例有限，但在多种人类癌症中可观察到PKC亚型水平异常。许多情况下，PKC表达改变还与疾病进展相关。
3. PKC最初被认为具有促有丝分裂作用，但该效应具有PKC同工酶特异性和细胞类型依赖性，因为多种PKC同时也能抑制细胞周期进程。研究显示若干PKC亚型通过上调细胞周期抑制因子，在多种细胞类型中发挥抗增殖作用。
4. PKCε通过增强Akt通路活性和上调促存活因子，在多种细胞类型中促进细胞存活。此外，PKCε过表达与多种细胞的化疗耐药性相关。
5. PKCδ通常被视为生长抑制性或促凋亡PKC，多种凋亡刺激可诱导PKCδ向线粒体转位，导致细胞色素c释放、caspase-3切割，并生成持续活化的PKCδ催化片段，该片段对核内PKC底物的磷酸化至关重要。PKCδ激活还能触发死亡因子的自分泌分泌，通过外源性凋亡通路导致细胞死亡。
6. 若干PKC亚型与癌细胞的侵袭和转移相关，但关于PKC参与这些过程的分子机制仍不明确。
7. 新近证据表明PKC（特别是PKCβII）可能是血管内皮生长因子诱导血管生成的关键介质，并在VEGF诱导的内皮细胞增殖中发挥作用。
8. 佛波酯或二酰甘油还能激活其他几类蛋白质，包括蛋白激酶D、Ras鸟苷酸释放蛋白、嵌合蛋白、二酰甘油激酶和Munc13蛋白，其中多种蛋白已被证实与癌症进展相关。

英文摘要：

Almost three decades after the discovery of protein kinase C (PKC), we still have only a partial understanding of how this family of serine/threonine kinases is involved in tumour promotion. PKC isozymes — effectors of diacylglycerol (DAG) and the main targets of phorbol-ester tumour promoters — have important roles in cell-cycle regulation, cellular survival, malignant transformation and apoptosis. How do PKC isozymes regulate these diverse cellular processes and what are their contributions to carcinogenesis? Moreover, what is the contribution of all phorbol-ester effectors, which include PKCs and small G-protein regulators? We now face the challenge of dissecting the relative contribution of each DAG signal to cancer progression.

摘要翻译： 

在蛋白激酶C（PKC）发现近三十年后，我们对这一丝氨酸/苏氨酸激酶家族如何参与肿瘤促进仍只有部分了解。PKC同工酶——二酰甘油（DAG）的效应因子和佛波酯肿瘤促进剂的主要靶点——在细胞周期调控、细胞存活、恶性转化和凋亡中发挥重要作用。PKC同工酶如何调控这些多样的细胞过程？它们对致癌作用有何贡献？此外，所有佛波酯效应因子（包括PKC和小G蛋白调节因子）的贡献又是什么？我们现在面临的挑战是剖析每种DAG信号对癌症进展的相对贡献。

原文链接：

Protein kinase C and other diacylglycerol effectors in cancer