Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation.
Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation.
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DOI：
10.1371/journal.pone.0045330
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Natarajan V
中科院分区：
文献类型：
--
作者：
Kalari S;Moolky N;Pendyala S;Berdyshev EV;Rolle C;Kanteti R;Kanteti A;Ma W;He D;Husain AN;Kindler HL;Kanteti P;Salgia R;Natarajan V
恶性胸膜间皮瘤（MPM）是一种毁灭性的疾病，总体预后不良。尽管最近在靶向分子治疗方面取得了进展，但仍然迫切需要鉴定新的间皮瘤靶点以开发高效的治疗方法。在这项研究中，我们报告，鞘氨醇激酶1（SphK 1）蛋白的表达优先MPM肿瘤组织（49上皮样和肉瘤样）相比，正常组织（n = 13）升高。 此外，我们还观察到与非恶性间皮细胞Met 5细胞相比，MPM细胞系如H2691、H513和H2461中SphK 1和SphK 2 mRNA以及SphK 1蛋白表达水平显著升高。潜在的机制似乎是由SphK 1诱导的选择基因转录程序如CBP/p300和PCAF，两种组蛋白乙酰基转移酶（HAT）的上调，以及细胞周期依赖性激酶抑制剂基因如p27 Kip 1和p21 Cip 1的下调介导的。此外，使用来自SphK抑制剂、SphK-I2处理的Met 5A和H2691细胞裂解物的抗乙酰化组蛋白抗体的免疫沉淀物，我们还显示了其他细胞增殖相关基因的激活，如Top 2A（DNA复制）、AKB（染色体重塑和有丝分裂纺锤体形成），以及p21 CIP 1和p27 KIP 1的抑制。然而，CDK 2、HAT 1和MYST 2在上述研究中未受影响。使用SphK抑制剂和靶向SphK 1或SphK 2的特异性siRNA，我们也明确地确定SphK 1而不是SphK 2促进H2691间皮瘤细胞增殖。使用多壁碳纳米管诱导的腹膜间皮瘤小鼠模型，我们发现SphK 1-/-null小鼠与野生型小鼠相比，炎症和肉芽肿结节明显减少。脂质激酶SphK 1在恶性间皮瘤的生长和发展中起着积极和重要的作用，因此是一个可能的治疗靶点。
Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics. In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1−/− null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts. The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
4.8
作者：
Kwon, YG;Min, JK;Kim, YM
通讯作者：
Kim, YM
影响因子：
3.2
作者：
Johnson, KR;Johnson, KY;Obeid, LM
通讯作者：
Obeid, LM
鞘氨醇激酶 1 调节 Akt/FOXO3a/Bim 通路并有助于胶质瘤细胞的凋亡抵抗
影响因子：
3.7
作者：
Guan H;Song L;Cai J;Huang Y;Wu J;Yuan J;Li J;Li M
通讯作者：
Li M
影响因子：
50.3
作者：
Kang-Decker, N;Tong, CL;van Deursen, JMA
通讯作者：
van Deursen, JMA