Weinstein I B, Begemann M, Zhou P, Han E K, Sgambato A, Doki Y, Arber N, Ciaparrone M, Yamamoto H
Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Clin Cancer Res. 1997 Dec;3(12 Pt 2):2696-702.
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.
恶性肿瘤的发展涉及多个具有高度多样化功能的基因逐步获得突变和表观遗传异常。其中一些基因编码介导生长因子作用的信号转导途径。酶蛋白激酶C在这些事件以及肿瘤促进过程中发挥重要作用。因此，我们研究了蛋白激酶C的三种抑制剂CGP 41251、RO 31 - 8220和钙泊三醇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凋亡；这些活性与CDC2水平的降低以及细胞周期蛋白B1/CDC2相关激酶活性的降低有关。这可能解释了为什么处理后的细胞在G2 - M期积累。在另一系列研究中，我们研究了人类癌症中细胞周期控制基因的异常情况。我们发现细胞周期蛋白D1在多种人类癌症中经常过度表达。机制研究表明，细胞周期蛋白D1在致癌过程中可能起关键作用，因为：过度表达增强细胞转化和肿瘤发生；将反义细胞周期蛋白D1 cDNA导入人食管癌或结肠癌细胞可使其恶性表型逆转；细胞周期蛋白D1的过度表达可增强其他基因的扩增。后一发现表明细胞周期蛋白D1可增强基因组不稳定性，从而促进肿瘤进展过程。因此，细胞周期蛋白D1功能的抑制剂可能在癌症化学预防和治疗中都有用。我们获得了细胞周期蛋白D1或E与细胞周期抑制蛋白p27Kip1之间存在稳态反馈环的证据。基于这些及其他发现，我们假设，由于其紊乱的电路，癌细胞患有“基因成瘾”和“基因超敏性”，这些紊乱可能在癌症预防和治疗中得到利用。
