The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide
The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide
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DOI：
10.1016/j.taap.2013.10.027
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发表时间：
2014-01-01
影响因子：
3.8
通讯作者：
Lin, Cheng-Wei
中科院分区：
文献类型：
--
作者：
Lee, Wen-Ying;Chen, Yen-Chou;Lin, Cheng-Wei
血红素加氧酶(HO)-1是一种氧化应激反应酶，可催化血红素降解为胆红素、铁离子和一氧化碳（CO）。据报道，HO-1的诱导具有抗肿瘤活性；然而，其抑制机制尚不清楚。在本研究中，我们发现用CO释放化合物[Ru(CO)(3)Cl-2](2) （RuCO）治疗可降低人MCF7和MDA-MB-231乳腺癌细胞的生长。生长相关蛋白分析显示，RuCO处理下调了cyclinD1、CDK4和hTERT蛋白的表达。有趣的是，RuCO治疗对野生型和突变型p53蛋白产生相反的作用。这些结果与格尔达霉素（一种热休克蛋白（HSP）90抑制剂）处理的细胞相似，表明RuCO可能影响HSP90的活性。此外，RuCO诱导突变型p53蛋白不稳定，并伴随泛素化和蛋白酶体降解的促进。钴原卟啉IX （CoPP）对HO-1的诱导效果一致，而HO-1酶抑制剂锡原卟啉IX （SnPP）的加入减弱了ruco介导的作用。p38丝裂原活化蛋白激酶抑制剂（SB203580）可降低RuCO对HO-1表达的诱导。此外，用化学预防化合物姜黄素治疗可诱导HO-1表达，同时降低HSP90客户蛋白表达。姜黄素对HO-1的诱导抑制了TPA诱导的基质金属蛋白酶-9的表达和肿瘤侵袭。总之，我们为HO-1的抗肿瘤机制提供了新的证据。CO是HO-1的副产物，可以抑制HSP90蛋白的活性，诱导HO-1可能具有治疗癌症的潜力。(C) 2013出版的爱思唯尔公司。
Heme oxygenase (HO)-1 is an oxidative stress-response enzyme which catalyzes the degradation of heme into bilirubin, ferric ion, and carbon monoxide (CO). Induction of HO-1 was reported to have antitumor activity; the inhibitory mechanism, however, is still unclear. In the present study, we found that treatment with [Ru(CO)(3)Cl-2](2) (RuCO), a CO-releasing compound, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells. Analysis of growth-related proteins showed that treatment with RuCO down-regulated cyclinD1, CDK4, and hTERT protein expressions. Interestingly, RuCO treatment resulted in opposite effects on wild-type and mutant p53 proteins. These results were similar to those of cells treated with geldanamycin (a heat shock protein (HSP)90 inhibitor), suggesting that RuCO might affect HSP90 activity. Moreover, RuCO induced mutant p53 protein destabilization accompanied by promotion of ubiquitination and proteasome degradation. The induction of HO-1 by cobalt protoporphyrin IX (CoPP) showed consistent results, while the addition of tin protoporphyrin IX (SnPP), an HO-1 enzymatic inhibitor, diminished the RuCO-mediated effect. RuCO induction of HO-1 expression was reduced by a p38 mitogen-activated protein kinase inhibitor (SB203580). Additionally, treatment with a chemopreventive compound, curcumin, induced HO-1 expression accompanied with reduction of HSP90 client protein expression. The induction of HO-1 by curcumin inhibited 12-O-tetradecanoyl-13-acetate (TPA)-elicited matrix metalloproteinase-9 expression and tumor invasion. In conclusion, we provide novel evidence underlying HO-1's antitumor mechanism. CO, a byproduct of HO-1, suppresses HSP90 protein activity, and the induction of HO-1 may possess potential as a cancer therapeutic. (C) 2013 Published by Elsevier Inc.