Involvement of protein kinase C in phorbol ester-induced sensitization of HeLa cells to cis-diamminedichloroplatinum(II).
Involvement of protein kinase C in phorbol ester-induced sensitization of HeLa cells to cis-diamminedichloroplatinum(II).
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DOI：
10.1016/s0021-9258(19)38909-4
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发表时间：
1990-05
期刊：
影响因子：
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通讯作者：
A. Basu;B. Teicher;J. Lazo
中科院分区：
文献类型：
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作者：
A. Basu;B. Teicher;J. Lazo
我们已经研究了促进肿瘤的佛波醇酯对几种抗肿瘤药物的抗增殖作用的影响。用12-O-十四烷酰基佛波醇13-乙酸酯（TPA）或佛波醇12，13-二丁酸酯（PDBu）预处理HeLa细胞引起细胞对顺式二氨二氯铂（II）（CP）的敏感性显著增加（9倍）。TPA也使HeLa细胞对美法仑敏感（2.5倍），但对博莱霉素、阿霉素、长春新碱或丝裂霉素C的抗增殖活性没有影响。TPA对HeLa细胞的致敏作用是浓度依赖性的，最高可达1 nM，并且抑制了TPA对蛋白激酶C的激活作用。使用10 nM TPA观察到蛋白激酶C的最大刺激（6倍）。4 α-佛波醇12，13-二癸酸酯既不激活蛋白激酶C，也不使HeLa细胞对CP敏感。4-O-甲基-TPA不影响HeLa细胞的细胞周期分布，也使这些细胞对CP敏感6倍，并使蛋白激酶C活化3倍。蛋白激酶C的抑制剂，如棕榈酰肉毒碱和鞘氨醇，拮抗PDBu-induced致敏HeLa细胞CP。HeLa细胞对CP的最大致敏需要长时间的佛波醇酯预处理（大于或等于24小时），但不能用蛋白激酶C的下调来解释。例如，4-O-甲基-TPA不引起蛋白激酶C的下调。此外，TPA导致A-253细胞中蛋白激酶C的显著下调（对照的1%），但未能使A-253细胞对CP敏感。然而，TPA（100 nM）可将A-253细胞中的蛋白激酶C激活5.5倍。因此，TPA激活蛋白激酶C似乎是必要的，但不足以使细胞对CP敏感。TPA对HeLa细胞的致敏作用与细胞铂含量的浓度和时间依赖性增加有关。蛋白质合成抑制剂放线菌酮（10微克/毫升）阻断HeLa细胞的敏感性CP以及铂含量的增加所造成的24小时预处理PDBu。
We have investigated the effect of tumor promoting phorbol esters on the antiproliferative actions of several antitumor agents. Pretreatment of HeLa cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) or phorbol 12,13-dibutyrate (PDBu) caused a significant (9-fold) increase in cellular sensitivity to cis-diamminedichloroplatinum(II) (CP). TPA also sensitized HeLa cells to melphalan (2.5-fold) but had no effect on the antiproliferative activity of bleomycin, doxorubicin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was concentration-dependent up to 1 nM and paralleled the activation of protein kinase C by TPA measured in vitro. The maximum stimulation of protein kinase C (6-fold) was observed with 10 nM TPA. 4 alpha-Phorbol 12,13-didecanoate neither activated protein kinase C nor sensitized HeLa cells to CP. 4-O-Methyl-TPA, which does not affect cell cycle distribution of HeLa cells, also sensitized these cells to CP by 6-fold and activated protein kinase C by 3-fold. Inhibitors of protein kinase C, such as palmitoylcarnitine and sphingosine, antagonized PDBu-induced sensitization of HeLa cells to CP. The maximum sensitization of HeLa cells to CP required prolonged pretreatment (greater than or equal to 24 h) with phorbol esters but could not be explained by down-regulation of protein kinase C. For example, 4-O-methyl-TPA caused no down-regulation of protein kinase C. Moreover, TPA caused substantial down-regulation of protein kinase C (1% of control) in A-253 cells but failed to sensitize A-253 cells to CP. TPA (100 nM), however, activated protein kinase C in A-253 cells by 5.5-fold. Therefore, activation of protein kinase C by TPA appears to be necessary but not sufficient for cellular sensitization to CP. The sensitization of HeLa cells by TPA was associated with a concentration- and time-dependent increase in cellular platinum content. The protein synthesis inhibitor cycloheximide (10 micrograms/ml) blocked sensitization of HeLa cells to CP as well as the increase in platinum content caused by a 24-h pretreatment with PDBu.