Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway
Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway
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DOI：
10.1016/j.biocel.2006.03.013
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Alcaraz, Maria Jose
中科院分区：
文献类型：
--
作者：
Busserolles, Jerome;Megias, Javier;Alcaraz, Maria Jose
血红素氧合酶-1对细胞应激具有保护作用。在结肠癌细胞中，这些作用与肿瘤发生和对化疗的抵抗有关。该研究的目的是检查血红素加氧酶-1诱导对人结肠癌细胞系Caco-2中细胞存活的影响。血清剥夺诱导细胞凋亡，减少Akt和p38磷酸化，并增加p21（Cip/WAF 1）水平。血红素加氧酶-1诱导治疗钴原卟啉IX导致抗凋亡，激活Akt，减少p21 Cip/WAF 1水平和修改bcl 2/bax的比例对生存。吲哚美辛减少细胞凋亡，但与血红素加氧酶-1相反，将细胞阻滞在G 0/G1期。血红素加氧酶代谢产物胆红素和胆绿素也抑制细胞凋亡，但CO供体三羰基二氯钌（II）二聚体没有发挥显着的作用。通过与血红素加氧酶-1小干扰RNA一起孵育，用钴原卟啉IX处理的细胞中的抗凋亡保护被逆转。这项研究表明，血红素加氧酶-1在结肠癌细胞中的抗凋亡作用，这可能是由胆红素和胆绿素的形成介导的。我们的研究结果支持HO-1在这些细胞中的抗凋亡作用，并提供了一种机制，HO-1的过表达可能会促进肿瘤在营养供应有限的条件下对应激的抵抗力。我们已经扩展了这些观察，证明这些影响是独立的p38，但介导的Akt途径。(c)2006爱思唯尔有限公司版权所有。
Heme oxygenase-1 can play a protective role against cellular stress. In colon cancer cells, these effects would be relevant to oncogenesis and resistance to chemotherapy. The aim of the study was to examine the effects of heme oxygenase-1 induction on cell survival in a human colon cancer cell line, Caco-2. Serum deprivation induced apoptosis, reduced Akt and p38 phosphorylation, and increased p21(Cip/WAF1) levels. Heme oxygenase-1 induction by treatment with cobalt protoporphyrin IX resulted in resistance to apoptosis, activation of Akt, reduction in p21Cip/WAF1 levels and modification of bcl2/bax ratio towards survival. Indomethacin reduced apoptosis but in contrast to heme oxygenase-1, arrested cells in G0/G1. Apoptosis was also inhibited by the heme oxygenase metabolites bilirubin and biliverdin but the CO donor tricarbonyldichlororuthenium(II) dimer did not exert significant effects. Protection against apoptosis in cells treated with cobalt protoporphyrin IX was reverted by incubation with heme oxygenase-1 small interfering RNA. This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin. Our results support an antiapoptotic role for HO-1 in these cells and provide a mechanism by which overexpression of HO-1 may promote tumor resistance to stress in conditions of limited nutrient supply. We have extended these observations by demonstrating that these effects are independent of p38 but are mediated via Akt pathway. (c) 2006 Elsevier Ltd. All rights reserved.