Antagonism between epidermal growth factor and phorbol ester tumor promoters in human breast cancer cells.
Antagonism between epidermal growth factor and phorbol ester tumor promoters in human breast cancer cells.
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人乳腺癌细胞中表皮生长因子和佛波酯肿瘤促进剂之间的拮抗作用。
DOI：
10.1172/jci110144
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发表时间：
1981
期刊：
影响因子：
--
通讯作者：
Ziegler,J
中科院分区：
文献类型：
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作者：
Osborne,CK;Hamilton,B;Nover,M;Ziegler,J
已有研究表明佛波酯类肿瘤促进剂通过表皮生长因子受体效应系统发挥作用，因为它们与表皮生长因子受体系统相互作用，并在培养细胞中模拟EGF的许多作用。我们研究了佛波酯与EGF敏感的人乳腺癌细胞株MCF-7的相互作用。与其他系统类似，佛波酯抑制MCF-7细胞中EGF的结合，其方式与其在小鼠中作为肿瘤促进剂的效力平行。这种作用是EGF所特有的，因为胰岛素的膜结合不受影响。与EGF一样，强效佛波酯12-O-十四酰-13-佛波酯(TPA)可刺激蛋白质合成，TPA作用24小时后[~3H]亮氨酸掺入蛋白质的量增加一倍。然而，细胞形态与TPA处理有显著不同。TPA作用24-48h后，细胞明显增大，胞质空泡化增加，膜微绒毛增多。这反映在蛋白质/DNA比例增加了四倍(对照13.1；TPA 55.9)。此外，TPA在有或无血清的培养液中抑制细胞分裂，并阻止EGF对细胞生长的刺激。低浓度的TPA(1.0 ng/ml)是有效的，10 ng/ml的TPA对细胞复制有最大的抑制作用。其他佛波酯抑制MCF-7细胞的作用与其体内肿瘤促进活性和抑制这些细胞中EGF结合的能力有关。TPA作用24小时后，[~3H]胸腺嘧啶核苷掺入明显减少，标记指数下降(33%~2%)，表明S期细胞很少。通过从培养基中去除TPA，生长抑制是可逆的。另外两个被研究的人乳腺癌细胞株ZR75-1和MDA-MB-231也有类似的抑制作用。总之，佛波酯可能与MCF-7人乳腺癌细胞中的EGF受体结构域相互作用，但它们对细胞形态和生长有不同的影响，提示了不同的作用途径。这些化合物的抗肿瘤活性需要进一步研究。
It has been suggested that the phorbol ester tumor promoters act via the receptor-effector system for epidermal growth factor (EGF), since they interact with the EGF receptor system and mimic many of the effects of EGF in cultured cells. We have studied the interaction of phorbol esters with the EGF-responsive MCF-7 human breast cancer cell line. Similar to other systems, phorbol esters inhibit EGF binding in MCF-7 cells in a manner paralleling their potency as tumor promoters in mice. The effect is specific for EGF since the membrane binding of insulin is unaffected. Like EGF, the potent phorbol ester 12-O-tetradecanoyl-13-phorbol acetate (TPA) stimulates protein synthesis as indicated by a twofold increase in [3H]leucine incorporation into protein after 24 h in TPA. Cell morphology, however, is significantly different with TPA treatment. After 24-48 h in TPA, cells become markedly enlarged with increased cytoplasmic vacuolization and increased membrane microvilli. This is reflected in a fourfold increase in the protein/DNA ratio (control 13.1; TPA 55.9). Furthermore, TPA inhibits cell division in media with or without serum, and prevents growth stimulation by EGF. Low TPA concentrations (1.0 ng/ml) are active, and 10 ng/ml results in maximal inhibition of cell replication. Other phorbol esters inhibit MCF-7 cells relative to their tumor promoting activity in vivo and their ability to inhibit EGF binding in these cells. After 24 h in TPA, incorporation of [3H]thymidine into DNA is markedly reduced and the thymidine labeling index falls (33% to 2%) indicating very few S-phase cells. Growth inhibition is reversible by removing TPA from the medium. Similar inhibitory effects are seen with the two other human breast cancer cell lines studied, ZR75-1 and MDA-MB-231. In conclusion, phorbol esters may interact with the EGF receptor domain in MCF-7 human breast cancer cells, but they have distinct effects on cell morphology and growth suggesting alternative pathways of action. The antineoplastic activity of these compounds needs further investigation.Images