T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells
T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells
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DOI：
10.1158/1541-7786.mcr-13-0485
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发表时间：
2014-03-01
影响因子：
5.2
通讯作者：
Dziegielewski, Jaroslaw
中科院分区：
文献类型：
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作者：
Dziegielewska, Barbara;Brautigan, David L.;Dziegielewski, Jaroslaw
上皮肿瘤细胞表达T型Ca 2+通道，其被认为促进细胞增殖。本研究探讨了细胞对小分子拮抗剂或RNAi介导的敲除抑制T型Ca 2+通道的反应。选择性T型钙通道拮抗剂在表达野生型p53（p53 wt）的HCT 116细胞中比在HCT 116突变型p53（-/-）细胞中更有效地引起生长抑制和凋亡。这些拮抗剂增加了p53依赖性基因表达，并增加了p53在特定靶序列的基因组占有率。与HCT 116突变型p53（-/-）细胞相比，在HCT 116 p53 wt细胞中敲低单个T型Ca 2+通道亚基（CACNA 1G）降低细胞生长并诱导caspase-3/7活化。此外，当p53 wt稳定表达时，不表达功能性p53的CaCo 2细胞对CACNA 1G敲低更敏感。在T型Ca ~（2+）通道抑制后，p38-MAPK促进p53 wt的Ser 392磷酸化。用抑制剂SB 203580或靶向p38-MAPK α/β（MAPK 14/MAPK 11）的特异性RNAi处理的细胞显示出对T型Ca 2+通道抑制的抗性。最后，对通道抑制的敏感性降低与p53积累减少和p53靶基因p21 Cip 1（CDKN 1A）和BCL 2结合组分3（BBC 3/CDKN 1A）表达减少有关。（C）2013年AACR。
Epithelial tumor cells express T-type Ca2+ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca2+ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca2+ channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53(-/-) cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca2+ channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53(-/-) cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca2+ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPK alpha/beta (MAPK14/MAPK11) showed resistance to T-type Ca2+ channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA). (C)2013 AACR.