Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis.
Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis.
复制标题
TSA 通过抑制 HDAC3 和 HDAC7 诱导自分泌运动因子，并拮抗 TSA 诱导的细胞凋亡
DOI：
10.1186/1476-4598-10-18
复制
发表时间：
2011-02-12
期刊：
影响因子：
37.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Li S;Wang B;Xu Y;Zhang J
背景自分泌运动因子（Autotaxin，ATX）是一种分泌型糖蛋白，具有溶血磷脂酶D（lysoPLD）活性，可将溶血磷脂酰胆碱（LPC）转化为溶血磷脂酸（LPA），后者是一种具有生物活性的溶血磷脂，参与多种生物学作用。ATX在一些癌细胞中高度表达并有助于其肿瘤发生、侵袭和转移，而在其他癌细胞中ATX沉默或以低水平表达。ATX在癌细胞中的表达调控的机制仍然在很大程度上unknown.ResultsIn本研究中，我们证明，阿司他丁A（TSA），一个众所周知的HDAC抑制剂（HDACi），显着诱导ATX表达在SW 480和其他几个癌细胞低或检测不到内源性ATX表达。当HDAC 3和HDAC 7被它们的siRNA下调时，可以观察到ATX诱导。发现HDAC 7表达水平在具有高内源性ATX表达的癌细胞中是低的。HDAC 7的外源性过表达以HDAC 3依赖的方式抑制这些细胞中的ATX表达。这些数据表明HDAC 3和HDAC 7协同抑制癌细胞中的ATX表达，并且表明TSA通过抑制HDAC 3和HDAC 7诱导ATX表达。揭示了这种调节机制的生物学意义表明，TSA诱导的ATX保护癌细胞对TSA诱导的凋亡产生LPA通过其lysoPLD活性，这可以逆转的BrP-LPA和S32826，ATX-LPA axills.ConclusionsWe的抑制剂表明，ATX的表达被抑制的HDAC 3和HDAC 7在癌细胞中。在TSA处理期间，ATX由于HDAC 3和HDAC 7抑制而被诱导，并且在功能上拮抗TSA诱导的细胞凋亡。这些结果揭示了癌细胞中的内部HDACi耐药机制，并表明ATX-LPA轴的抑制将有助于提高基于HDACi的治疗剂对癌症的疗效。
BackgroundAutotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown.ResultsIn the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis.ConclusionsWe have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer.
登录
查看更多内容
影响因子：
8
作者：
Kim, J. K.;Samaranayake, M.;Pradhan, S.
通讯作者：
Pradhan, S.
影响因子：
11.5
作者：
Fantin, Valeria R.;Richon, Victoria M.
通讯作者：
Richon, Victoria M.
影响因子：
4
作者：
Jansen, S;Stefan, C;Bollen, M
通讯作者：
Bollen, M
DOI：
10.1124/jpet.108.141911
发表时间：
2008-12-01
影响因子：
3.5
作者：
Ferry, Gilles;Moulharat, Natacha;Boutin, Jean A.
通讯作者：
Boutin, Jean A.
影响因子：
4.8
作者：
Li, XF;Song, S;Kao, HY
通讯作者：
Kao, HY