Enhanced retinoid-induced apoptosis of MDA-MB-231 breast cancer cells by PKC inhibitors involves activation of ERK
Enhanced retinoid-induced apoptosis of MDA-MB-231 breast cancer cells by PKC inhibitors involves activation of ERK
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DOI：
10.1038/sj.onc.1207956
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发表时间：
2004-09
期刊：
影响因子：
8
通讯作者：
F. Pettersson;Marie-Claude Couture;N. Hanna;W. Miller
中科院分区：
文献类型：
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作者：
F. Pettersson;Marie-Claude Couture;N. Hanna;W. Miller
类维生素A是维生素A的衍生物，可导致多种细胞类型的生长抑制、分化和/或凋亡，包括一些乳腺癌细胞。一般来说，雌激素受体（ER）阳性的细胞对维甲酸（RA）敏感，而雌激素受体阴性的细胞则耐药。在本报告中，我们发现er阴性的MDA-MB-231细胞被类维生素a与PKC抑制剂联合强烈抑制生长。虽然RA和GF109203X （GF）在这些细胞中都没有明显的生长抑制作用，但RA+ GF能有效抑制细胞增殖。我们发现RA+ GF诱导细胞凋亡，表现为DNA片段增加，annexin - v阳性细胞增加，caspase-3活化增加。GF联合两种合成类维生素a也可诱导细胞凋亡。GF降低了磷酸化PKC和总PKC的表达，RA增强了这一作用。此外，GF治疗引起ERK1/2和p38-MAPK的强烈和持续激活，以及JNK的较弱激活。重要的是，抑制ERK而不抑制p38或JNK可抑制RA+ GF诱导的细胞凋亡，这表明ERK的激活是特异性需要的。为了支持这一新发现，其他PKC抑制剂与RA联合引起细胞凋亡的能力与引起ERK持续激活的能力相关。
Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor (ER)-positive cells are retinoic acid (RA) sensitive, whereas ER-negative cells are resistant. In this report, we show that ER-negative MDA-MB-231 cells are strongly growth inhibited by retinoids in combination with a PKC inhibitor. While neither RA nor GF109203X (GF) has a significant growth inhibitory effect in these cells, RA+ GF potently suppress proliferation. We found that RA+ GF induce apoptosis, as shown by an increase in fragmented DNA, Annexin-V-positive cells and caspase-3 activation. Apoptosis was also induced by GF in combination with two synthetic retinoids. Expression of phosphorylated as well as total PKC was decreased by GF and this was potentiated by RA. In addition, treatment with GF caused a strong and sustained activation of ERK1/2 and p38-MAPK, as well as a weaker activation of JNK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RA+ GF, indicating that activation of ERK is specifically required. In support of this novel finding, the ability of other PKC inhibitors to cause apoptosis in combination with RA correlates with ability to cause sustained activation of ERK.