Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells
Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells
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DOI：
10.1093/carcin/bgp223
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发表时间：
2009-11-01
期刊：
影响因子：
4.7
通讯作者：
Roberts-Thomson, Sarah J.
中科院分区：
文献类型：
--
作者：
Aung, Cho S.;Ye, Weilan;Roberts-Thomson, Sarah J.
钙稳态的重塑已被确定为某些癌症的特征性特征。其可能的后果包括改变许多关键的生理反应，包括细胞凋亡，增殖和基因转录。钙稳态的改变可以通过转运钙的蛋白质表达的变化而发生，并且可以看到的癌症的例子包括前列腺和乳腺癌。钙外排泵的一种特殊亚型，质膜Ca 2 +-ATP酶（PMCA）4，在HT-29结肠癌细胞系分化过程中显著上调，表明它也可能在结肠癌中发生改变。我们现在报告，分化的HT-29结肠癌细胞具有明显的质膜PMCA 4定位，与增加的钙外流一致。对人结肠癌样品中PMCA 4转录的评估表明，PMCA 4在一些结肠癌进展的早期显著（P < 0.000001）下调，因为这些细胞变得分化较低。使用小干扰RNA抑制PMCA 4不会诱导细胞死亡或增加对线粒体解偶联剂羰基氰3-氯苯腙（CCCP）或肿瘤坏死因子相关凋亡诱导配体的敏感性。PMCA 4过表达逆转结肠癌细胞重塑后，细胞增殖减少（P < 0.01），钙敏感早期反应基因FOS转录下调。我们的研究表明，在结肠癌中钙信号的重塑与受损的钙外流在促进增殖途径的水平，同时避免增加敏感性的凋亡刺激。
A remodeling of calcium homeostasis has been identified as a characterizing feature of some cancers. Possible consequences of this include alterations in many pivotal physiological responses including apoptosis, proliferation and gene transcription. An alteration in calcium homeostasis can occur via changes in the expression of proteins that transport calcium and examples of cancers where this is seen includes the prostate and breast. A specific isoform of the calcium efflux pump, plasma membrane Ca2+-ATPase (PMCA) 4, is significantly upregulated during differentiation of the HT-29 colon cancer cell line suggesting that it may also be altered in colon cancer. We now report that differentiated HT-29 colon cancer cells have pronounced plasma membrane PMCA4 localization, consistent with augmented calcium efflux. Assessment of PMCA4 transcription in human colon cancer samples suggests that PMCA4 is significantly (P < 0.000001) downregulated early in the progression of some colon cancers as these cells become less differentiated. Inhibition of PMCA4 using small interfering RNA did not induce cell death or augment sensitivity to the mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) or tumor necrosis factor-related apoptosis-inducing ligand. Reversing the colon cancer remodeling of PMCA4 by overexpression reduced cellular proliferation (P < 0.01) and downregulated transcription of the calcium sensitive early response gene FOS. Our studies suggest that the remodeling of the calcium signal in colon cancer is associated with compromised calcium efflux at a level that promotes proliferative pathways while avoiding increased sensitivity to apoptotic stimuli.