EFFECTS OF ACTIVATORS OF PROTEIN-KINASE C, INCLUDING BRYOSTATIN-1 AND BRYOSTATIN-2, ON THE GROWTH OF A549 HUMAN-LUNG CARCINOMA-CELLS
EFFECTS OF ACTIVATORS OF PROTEIN-KINASE C, INCLUDING BRYOSTATIN-1 AND BRYOSTATIN-2, ON THE GROWTH OF A549 HUMAN-LUNG CARCINOMA-CELLS
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DOI：
10.1002/ijc.2910430129
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发表时间：
1989-01-15
影响因子：
6.4
通讯作者：
GESCHER, A
中科院分区：
文献类型：
--
作者：
DALE, IL;GESCHER, A
佛波酯如1,2-O-十四酰基佛波醇-13-乙酸酯（TPA）在无毒浓度下抑制A549人肺癌细胞的生长，而蛋白激酶C（PKC）的生理配体的合成类似物1-油酰基-2-乙酰基甘油和1，2-二辛酰基甘油则不抑制。进行实验以检验其他PKC激活剂能够干扰A549细胞生长的假设。非phorboid肿瘤促进剂mezerein模仿TPA的生长抑制作用，因为它阻止生长5天，之后细胞在该试剂的持续存在下再次增殖。TPA作为生长抑制剂的效力是美泽瑞因的20倍。苔藓抑素1在10 nM和苔藓抑素2在100 nM也逮捕A549细胞的生长和抑制DNA复制，通过掺入[甲基3 H]-胸苷到细胞中测量。在用TPA、美泽瑞因或苔藓抑素孵育细胞的第一个小时期间，DNA合成抑制至对照值的90 - 75%。抑制的程度变化不大，在随后的5小时的孵育，之后，它进一步增加，在12小时内达到最大值。在浓度高于那些引起最大的生长抑制，草苔虫抑制素废除自己的抑制DNA合成和抗复制效果的TPA和mezerein。结果表明，除佛波醇酯外的PKC激活剂能够抑制A549细胞的生长。苔藓抑素不仅干扰A549细胞生长，而且还可以对抗PKC激活剂的生长抑制作用，推测是通过与与佛波酯受体位点分离的靶点相互作用。
Phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibit the growth of A549 human lung carcinoma cells at non-toxic concentrations, whereas 1-oleoyl-2-acetylglycerol and 1,2-dioctanoylglycerol, synthetic analogues of the physiological ligands of protein kinase C (PKC), do not. Experiments were conducted to test the hypothesis that other activators of PKC are capable of interfering with A549 cell growth. The non-phorboid tumour promotor mezerein mimicked the growth-inhibitory effect of TPA in that it arrested growth for 5 days, after which cells proliferated again in the continued presence of the agent. TPA was 20 times more potent as a growth inhibitor than was mezerein. Bryostatin 1 at 10 nM and bryostatin 2 at 100 nM also arrested A549 cell growth and inhibited DNA replication as measured by incorporation of [methyl3H]-thymidine into cells. Inhibition of DNA synthesis to between 90 and 75% of control values developed during the first hour of incubation of the cells with TPA, mezerein or the bryostatins. The extent of inhibition changed little during the subsequent 5 hr of incubation, after which it increased further to reach maximal values within 12 hr. At concentrations above those which caused maximal growth inhibition, the bryostatins abolished both their own inhibition of DNA synthesis and the anti-replicative effect of TPA and mezerein. The results show that activators of PKC other than phorbol esters are capable of inhibiting the growth of A549 cells. The bryostatins not only interfere with A549 cell growth but can also counter the growth-inhibitory effect of PKC activators, presumably via interaction with a target separate from the phorbol ester receptor site.