Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.
Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.
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发表时间：
1997-12
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通讯作者：
I. Weinstein;Martin Begemann;P. Zhou;Edward Kyu-Ho Han;Alessandro Sgambato;Y. Doki;N. Arber;M. Ciaparrone;Hirofumi Yamamoto
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作者：
I. Weinstein;Martin Begemann;P. Zhou;Edward Kyu-Ho Han;Alessandro Sgambato;Y. Doki;N. Arber;M. Ciaparrone;Hirofumi Yamamoto
恶性肿瘤的发展涉及到在具有高度不同功能的多个基因中逐渐获得突变和表观遗传学异常。其中一些基因编码了介导生长因子作用的信号转导途径。蛋白激酶C在这些事件和肿瘤促进过程中起着重要的作用。因此，我们研究了蛋白激酶C的三种抑制剂，CGP41251，RO31-8220和Calphostin C对人胶质母细胞瘤细胞的影响。这些化合物抑制生长并诱导细胞凋亡；这些活性与CDC2水平和细胞周期蛋白B1/CDC2相关的激酶活性降低有关。这可能解释了为什么处理后的细胞在G2-M细胞中积累。在另一系列单独的研究中，我们检查了人类癌症细胞周期控制基因的异常。我们发现细胞周期蛋白D1在多种人类肿瘤中经常过表达。机制研究表明，细胞周期蛋白D1在肿瘤发生中起关键作用，因为：过表达可促进细胞转化和肿瘤发生；将反义细胞周期蛋白D1cDNA导入人食道或结肠癌细胞可逆转其恶性表型；过表达细胞周期蛋白D1可促进其他基因的扩增。后者的发现表明，细胞周期蛋白D1可以增强基因组的不稳定性，从而促进肿瘤的进展过程。因此，细胞周期蛋白D1功能的抑制剂在癌症的化学预防和治疗中都可能是有用的。我们获得了在细胞周期抑制蛋白p27Kip1和细胞周期蛋白d1或E之间存在稳态反馈环的证据。在这些和其他发现的基础上，我们假设，由于癌细胞的无序电路，他们遭受“基因成瘾”和“基因过敏症”，这两种疾病可能被用于癌症预防和治疗。
The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.