Kawasaki Brian T, Hurt Elaine M, Kalathur Madhuri, Duhagon Maria Ana, Milner John A, Kim Young S, Farrar William L
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick (NCI-Frederick), National Institutes of Health,1050Boyles Street, Frederick, MD 21702, USA.
Prostate. 2009 Jun 1;69(8):827-37. doi: 10.1002/pros.20931.
Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.
近期证据表明，肿瘤起始细胞（TICs），也被称为癌症干细胞，是肿瘤起始和进展的原因；因此，它们是未来抗癌疗法开发的重要细胞群体。在本研究中，我们表明倍半萜内酯小白菊内酯（PTL）对从前列腺癌细胞系DU145、PC3、VCAP和LAPC4以及原发性前列腺TICs中分离出的前列腺TICs具有细胞毒性。此外，PTL抑制了小鼠异种移植中TIC驱动的肿瘤形成。使用包括蛋白质组学、活化转录因子谱和基因组学在内的综合分子分析方法，我们确定了PTL对前列腺癌细胞的影响。除了先前描述的PTL的作用外，我们还确定非受体酪氨酸激酶src以及许多src信号成分，包括：Csk、FAK、β1-抑制蛋白、FGFR2、PKC、MEK/MAPK、CaMK、ELK-1以及ELK-1依赖性基因是PTL作用的新靶点。此外，PTL改变了在前列腺癌中重要的转录因子的结合，包括：C/EBP-α、fos相关抗原-1（FRA-1）、HOXA-4、c-MYB、SNAIL、SP1、血清反应因子（SRF）、STAT3、X-box结合蛋白-1（XBP1）和p53。总之，我们表明PTL对前列腺TICs具有细胞毒性，并描述了PTL介导的细胞毒性的分子事件。因此，PTL是一种有前景的前列腺癌治疗药物。
