Weinstein I B, Arcoleo J, Backer J, Jeffrey A, Hsiao W L, Gattoni-Celli S, Kirschmeier P, Okin E
Princess Takamatsu Symp. 1983;14:59-74.
Carcinogenesis is a multistep process resulting from a complex interaction between multiple factors, both environmental and exogenous. In contract to initiating agents that act by damaging cellular DNA, the primary targets of the phorbol ester tumor promoters are membrane-associated receptors. We have proposed a stereochemical model to explain the interaction of these amphiphilic molecules, and of teleocidin and aplysiatoxin, with this receptor system. The model is consistent with evidence that a complex between protein kinase C and phospholipid is the actual receptor for these compounds. Recent data we have obtained with a compound present in tung oil, 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA), and twelve of its congener's (provided by Y. Ito et al.) are also consistent with our stereochemical model. We have studied phorbol ester receptors in a wide variety of tissue culture cell types. Our data, together with other findings, provide evidence for considerable receptor heterogeneity and this may relate to the pleiotropic effects of these compounds. We have found a case of "masked" receptors in a rat liver cell line and shown that it is due to a cell-associated esterase. Normal human melanocyte cultures contain phorbol ester receptors and this is of particular interest since these cells actually require these or related compounds for optimal growth (in collaboration with M. Eisinger). The receptor studies provide clues to how tumor promoters can, via inductive mechanisms, produce alterations in the structure and function of cell membranes. It is not known, however, how in the multistep carcinogenic process promoters enhance the eventual outgrowth of permanently altered tumor cells. We have found that TPA and teleocidin produce a marked enhancement of transformation of C3H 10T1/2 cells induced by transfection with h-ras human bladder cancer oncogene. These and other results are discussed in terms of the role of alterations in cellular oncogenes and transcriptional enhancer sequences during multistage carcinogenesis.
致癌作用是一个多步骤过程，由多种环境和外源性因素之间的复杂相互作用导致。与通过损伤细胞DNA起作用的起始剂不同，佛波酯肿瘤促进剂的主要靶标是膜相关受体。我们提出了一个立体化学模型来解释这些两亲分子以及杀鱼菌素和海兔毒素与该受体系统的相互作用。该模型与蛋白激酶C和磷脂之间的复合物是这些化合物的实际受体这一证据相一致。我们用桐油中存在的一种化合物12 - O - 十六烷酰基 - 16 - 羟基佛波醇 - 13 - 乙酸酯（HHPA）及其12种同系物（由Y. Ito等人提供）获得的最新数据也与我们的立体化学模型一致。我们在多种组织培养细胞类型中研究了佛波酯受体。我们的数据以及其他发现为相当大的受体异质性提供了证据，这可能与这些化合物的多效性作用有关。我们在大鼠肝细胞系中发现了一例“隐蔽”受体，并表明这是由于一种细胞相关酯酶所致。正常人黑素细胞培养物含有佛波酯受体，这特别令人感兴趣，因为这些细胞实际上需要这些或相关化合物才能实现最佳生长（与M. Eisinger合作）。受体研究为肿瘤促进剂如何通过诱导机制导致细胞膜结构和功能改变提供了线索。然而，在多步骤致癌过程中促进剂如何增强永久改变的肿瘤细胞的最终生长尚不清楚。我们发现，佛波酯（TPA）和杀鱼菌素能显著增强用h - ras人膀胱癌癌基因转染诱导的C3H 10T1/2细胞的转化。这些结果以及其他结果将根据细胞癌基因和转录增强子序列的改变在多阶段致癌过程中的作用进行讨论。
