Lotem J, Sachs L
Proc Natl Acad Sci U S A. 1979 Oct;76(10):5158-62. doi: 10.1073/pnas.76.10.5158.
The control of cell multiplication and differentiation by tumor-promoting phorbol esters including 12-O-tetradecanoylphorbol-13-acetate (TPA) has been studied with different clones of mouse myeloid leukemic cells, a line of human myeloid leukemic cells, and normal mouse bone marrow myeloblasts. TPA induced normal cell differentiation in one of the mouse leukemic clones and this was mediated by induction of the protein inducer of differentiation to macrophages or granulocytes (MGI) in the cells that then differentiated. Other mouse clones were not induced to differentiate by TPA. In one of these clones, TPA induced cell susceptibility to externally added MGI. This effect was not due to a general induction of susceptibility to all compounds because TPA did not induce susceptibility to lypopolysaccharide or dexamethasone in this clone. In the human leukemic cell line, TPA also induced differentiation with the induction of MGI activity and enhanced susceptibility to added MGI. It is suggested that the clonal differences in induction of MGI activity and increased susceptibility to MGI may be associated with differences in receptors for TPA and the ability of TPA to modify receptors for MGI. Studies with normal bone marrow cells have indicated that TPA stimulated MGI activity and also increased susceptibility of normal myeloblasts to induction of multiplication by MGI. The ability of different phorbol esters to produce these effects on normal myeloblasts and myeloid leukemic cells paralleled their ability to act as tumor promoters. The results indicate that a tumor promoter such as TPA can induce the production of and increase cell susceptibility to a normal regulator of cell multiplication and differentiation. TPA has pleiotropic effects. It is suggested that, by these mechanisms, TPA may thus act as a tumor promoter by increasing cell multiplication in initiated cells, induce differentiation in some cells, or inhibit differentiation in other cells, depending on which molecules are being regulated in the TPA-treated cells.
利用小鼠髓性白血病细胞的不同克隆、人髓性白血病细胞系以及正常小鼠骨髓成髓细胞，研究了包括12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）在内的促肿瘤佛波酯对细胞增殖和分化的控制作用。TPA可诱导其中一个小鼠白血病克隆中的正常细胞分化，这是通过诱导随后分化的细胞中向巨噬细胞或粒细胞分化的蛋白质诱导剂（MGI）来介导的。其他小鼠克隆未被TPA诱导分化。在其中一个克隆中，TPA诱导细胞对外部添加的MGI敏感。这种效应并非由于对所有化合物的敏感性普遍诱导，因为TPA在此克隆中并未诱导对脂多糖或地塞米松的敏感性。在人白血病细胞系中，TPA也通过诱导MGI活性诱导分化，并增强对添加的MGI的敏感性。提示MGI活性诱导和对MGI敏感性增加的克隆差异可能与TPA受体的差异以及TPA修饰MGI受体的能力有关。对正常骨髓细胞的研究表明，TPA刺激MGI活性，也增加正常成髓细胞对MGI诱导增殖的敏感性。不同佛波酯对正常成髓细胞和髓性白血病细胞产生这些效应的能力与其作为肿瘤促进剂的作用能力平行。结果表明，像TPA这样的肿瘤促进剂可诱导正常细胞增殖和分化调节因子的产生并增加细胞对其的敏感性。TPA具有多效性。提示通过这些机制，TPA可能通过增加起始细胞中的细胞增殖而作为肿瘤促进剂，在某些细胞中诱导分化，或在其他细胞中抑制分化，这取决于TPA处理的细胞中哪些分子受到调控。
