Fischer S M, Jasheway D W, Klann R C, Butler A P, Patrick K E, Baldwin J K, Cameron G S
University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957.
Cancer Res. 1989 Dec 1;49(23):6693-9.
The activation of protein kinase C, induction of ornithine decarboxylase (ODC), and hyperplasia have been suggested to be linked, sequential processes resulting from phorbol ester application to mouse skin. However, evidence is presented indicating that these events are not necessarily linked or dependent on one another and that significant differences exist in these responses between phorbol ester promotion sensitive (SSIN) and resistant (C57BL/6J) mice. The epidermis from SSIN mice treated with a single application of 12-O-tetradecanoylphorbol-13-acetate (TPA) displayed a large induction of ODC and a subsequent extensive hyperplasia. A second TPA treatment at 24 or 48 h after the first did not result in ODC induction (refractory state), and protein kinase C was shown to be down-regulated at these times. By 72 h, however, a responsive state had returned even through protein kinase C remained down-regulated. The epidermis of C57BL/6J responds to a single application of TPA with a level of ODC induction similar to that of the SSIN mice. Protein kinase C was down-regulated by approximately 75% after 24 h and was virtually completely down-regulated at 48 and 72 h (95-97%). In contrast to the above findings for the sensitive mice, however, little, if any, hyperplasia was produced. In addition, while a second TPA treatment at 24 h did not result in ODC induction (refractory state), hyperplasia did occur within 24 to 48 h. When the second TPA application was given 48 h after the first, at a time when protein kinase C was down-regulated, an overinduction of ODC occurred, as well as subsequent hyperplasia. Furthermore, a significant number of papillomas resulted when these increased treatment frequencies, i.e., once a day or every other day, were used to promote dimethylbenz(a)anthracene-initiated C57BL/6J mice. It is concluded that, while hyperplasia remains an apparent requirement for tumor promotion, the ODC induction following an initial TPA treatment is insufficient for or not causally related to this hyperplasia. In addition, subsequent ODC induction, at least in the C57BL/6J mouse, is probably not mediated by protein kinase C.
蛋白激酶C的激活、鸟氨酸脱羧酶（ODC）的诱导和细胞增生被认为是相互关联的连续过程，这是佛波酯作用于小鼠皮肤后产生的结果。然而，有证据表明这些事件不一定相互关联或相互依赖，并且在佛波酯促进敏感（SSIN）和抗性（C57BL/6J）小鼠之间，这些反应存在显著差异。单次应用12 - O - 十四酰佛波醇 - 13 - 乙酸酯（TPA）处理的SSIN小鼠表皮显示出ODC的大量诱导以及随后广泛的细胞增生。在第一次处理后24或48小时进行第二次TPA处理并未导致ODC诱导（不应期），并且此时蛋白激酶C被证明下调。然而，到72小时时，即使蛋白激酶C仍然下调，反应状态已经恢复。C57BL/6J小鼠的表皮对单次应用TPA的反应是ODC诱导水平与SSIN小鼠相似。24小时后蛋白激酶C下调约75%，在48和72小时时几乎完全下调（95 - 97%）。然而，与上述敏感小鼠的发现相反，几乎没有产生细胞增生（如果有也是极少的）。此外，虽然在24小时进行第二次TPA处理未导致ODC诱导（不应期），但在24至48小时内确实发生了细胞增生。当在第一次处理后48小时给予第二次TPA应用时，此时蛋白激酶C已下调，ODC出现过度诱导以及随后的细胞增生。此外，当使用这些增加的处理频率，即每天一次或隔天一次，来促进二甲基苯并(a)蒽引发的C57BL/6J小鼠时，产生了大量乳头状瘤。得出的结论是，虽然细胞增生仍然是肿瘤促进的一个明显必要条件，但初始TPA处理后的ODC诱导不足以导致或与这种细胞增生没有因果关系。此外，至少在C57BL/6J小鼠中，随后的ODC诱导可能不是由蛋白激酶C介导的。
