Resveratrol regulates cellular PKC α and δ to inhibit growth and induce apoptosis in gastric cancer cells
Resveratrol regulates cellular PKC α and δ to inhibit growth and induce apoptosis in gastric cancer cells
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DOI：
10.1007/s10637-005-5855-8
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发表时间：
2005-01-01
影响因子：
3.4
通讯作者：
Holian, O
中科院分区：
文献类型：
--
作者：
Atten, MJ;Godoy-Romero, E;Holian, O
白藜芦醇是一种膳食植物抗菌素，由于其对癌细胞的抗增殖和促凋亡作用以及其抑制动物肿瘤生长的能力，已成为一种有前途的化学预防剂。白藜芦醇对胃腺癌细胞的作用是抑制DNA合成、激活一氧化氮合酶、诱导细胞凋亡、抑制总PKC和PKC α活性。在这里，我们证明了用白藜芦醇治疗胃腺癌scn -1细胞导致肿瘤抑制因子p21(（cip1)/(WAF-1)）和p53的时间和浓度依赖性积累，并且在此之前，膜相关PKC δ蛋白的丢失和伴随的细胞质PKC α的增加。细胞周期在S期到G(2)/M期的阻滞与h -3胸腺嘧啶的结合和p21（(cip1/WAF-1)）的积累有关，并暂时依赖于p53的增加。SNU-1细胞对白藜芦醇处理的反应是Fas和Fas- l蛋白上调，而在缺失p53的kto - iii细胞中，白藜芦醇处理后只有Fas- l蛋白升高。尽管在低浓度白藜芦醇处理24小时内，SNU-1细胞中的Fas和Fas- l蛋白以及kto - iii细胞中的Fas- l蛋白升高，但在这些浓度下仅在48小时后才观察到显著的凋亡反应。总之，我们的研究结果表明，白藜芦醇在上调抗增殖和促凋亡信号之前，参与胃腺癌SNU-1细胞中的PKC α和δ信号。白藜芦醇参与的特定细胞死亡信号似乎依赖于细胞类型，这表明白藜芦醇即使在发生突变变化后也具有化学预防潜力。
Resveratrol, a dietary phytoalexin, has emerged as a promising chemopreventive agent due to its antiproliferative and pro-apoptotic action toward cancer cells and its ability to inhibit tumor growth in animals. Gastric adenocarcinoma cells respond to resveratrol treatment with suppression of DNA synthesis, activation of nitric oxide synthase, induction of apoptosis and inhibition of total PKC and PKC alpha activity. Here we demonstrate that treatment of gastric adenocarcinoma SNU-1 cells with resveratrol results in time and concentration dependent accumulation of tumor suppressors p21((cip1)/(WAF-1)) and p53 and is preceded by loss of membrane-associated PKC delta protein and a concomitant increase in cytosolic PKC alpha. Arrest of the cell cycle at transition of S to G(2)/M phases correlates with the profile of H-3-thymidine incorporation and accumulation of p21((cip1/WAF-1)) and was temporally dependent on increase of p53. SNU-1 cells respond to resveratrol treatment with up-regulation of both Fas and Fas-L proteins, whereas in KATO-III cells, with deleted p53, only Fas-L is increased after resveratrol treatment. Although Fas and Fas-L proteins in SNU-1 cells and Fas-L in KATO-III cells were elevated within 24 h of cell treatment with low concentrations of resveratrol, significant apoptotic response at these concentrations was observed only after 48 h. Altogether, our findings indicate that resveratrol engages PKC alpha and delta signals in gastric adenocarcinoma SNU-1 cells prior to up-regulation of antiproliferative and pro-apoptotic signals. The specific cell death signals engaged by resveratrol appear to be cell type dependent and suggest that resveratrol has chemopreventive potential even after mutational changes have occurred.