Fésüs L, Szondy Z, Uray I
Department of Biochemistry, University Medical School of Debrecen, Hungary.
J Cell Biochem Suppl. 1995;22:151-61. doi: 10.1002/jcb.240590820.
This paper provides a rational molecular basis for studies intended to clarify the interactions between cancer chemopreventive agents and apoptosis, one of the natural forms of cell death that overlaps molecular mechanisms with other forms such as programmed cell death and specialized forms of physiological cell death. Molecular details of the process show the existence of distinct molecular pathways leading to the activation of critical effector elements (apoptosis gene products) functioning under the control of a network of negative regulatory elements. Dysregulation of either apoptosis or anti-apoptosis genes has a significant role in multistage carcinogenesis. Inhibition of apoptosis is one of the underlying mechanisms of the action of tumor promoters. The network of apoptosis and anti-apoptosis gene products provides multiple targets for compounds with cancer chemopreventive potential. Many data in the literature show initiating, potentiating or inhibitory effects of such compounds on apoptosis. However, the molecular mechanism of these effects is largely unknown. We initiated a series of studies using mouse thymocytes which undergo apoptosis through distinct molecular mechanisms after T-cell receptor activation (TCR pathway), following the addition of glucocorticoids (DEX pathway) or DNA damaging agents (p53 pathway). All trans-and 9-cis-retinoic acid induced apoptosis, elicited through the DEX pathway, inhibited the TCR pathway, and did not affect p53- initiated apoptosis. N-acetylcysteine can inhibit all forms. Sodium salicylate enhanced spontaneous cell death, decreased p53-dependent apoptosis, and did not affect the DEX and TCR pathways. These preliminary results, which show differential effects of the studied compounds on distinct molecular pathways of apoptosis, warrant further investigations in the effort to utilize the molecular elements of apoptosis in proper cancer chemoprevention, and find biochemical targets for apoptosis-related surrogate endpoint biomarker assays of chemoprevention.
本文为旨在阐明癌症化学预防剂与细胞凋亡之间相互作用的研究提供了合理的分子基础。细胞凋亡是细胞死亡的自然形式之一，它与程序性细胞死亡和生理性细胞死亡的特殊形式等其他形式在分子机制上存在重叠。该过程的分子细节表明，存在不同的分子途径导致关键效应元件（凋亡基因产物）的激活，这些元件在负调控元件网络的控制下发挥作用。凋亡基因或抗凋亡基因的失调在多阶段致癌过程中起着重要作用。抑制细胞凋亡是肿瘤促进剂作用的潜在机制之一。凋亡和抗凋亡基因产物网络为具有癌症化学预防潜力的化合物提供了多个靶点。文献中的许多数据表明此类化合物对细胞凋亡具有启动、增强或抑制作用。然而，这些作用的分子机制在很大程度上尚不清楚。我们启动了一系列研究，使用小鼠胸腺细胞，这些细胞在T细胞受体激活（TCR途径）后、添加糖皮质激素（DEX途径）或DNA损伤剂（p53途径）后通过不同的分子机制发生凋亡。全反式和9-顺式视黄酸诱导的凋亡是通过DEX途径引发的，抑制了TCR途径，并且不影响p53启动的凋亡。N-乙酰半胱氨酸可以抑制所有形式的凋亡。水杨酸钠增强了自发细胞死亡，减少了p53依赖性凋亡，并且不影响DEX和TCR途径。这些初步结果表明所研究的化合物对细胞凋亡的不同分子途径具有不同的作用，这为在适当的癌症化学预防中利用细胞凋亡的分子元件以及寻找化学预防中与凋亡相关的替代终点生物标志物检测的生化靶点提供了进一步研究的依据。
