Drug Discovery Department, Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
1] Drug Discovery Department, Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA [2] Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA [3] Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
Br J Cancer. 2014 Aug 26;111(5):894-902. doi: 10.1038/bjc.2014.349. Epub 2014 Jul 1.
The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anticancer agents.
Co-immunoprecipitation, western blotting, microscopy, DNA binding, invasion, and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin (Wit) inhibits STAT 3/5 tyrosine phosphoryaltion and activation.
Wit blocks EGF- and IL-6-stimulated binding of STAT3 and STAT5 to EGFR and gp130. Wit inhibits EGF-, PDGF-, IL-6-, IFNβ-, and GM-CSF-stimulation of tyrosine phosphorylation of STAT3 and STAT5 but not of EGFR or PDGFR. The inhibition of P-STAT3 and P-STAT5 occurred rapidly, within minutes of Wit treatment and growth factor stimulation. Wit also inhibits STAT3 nuclear translocation, DNA binding, promoter transcriptional activation, and it suppresses the expression levels of STAT3 target genes such as Bcl-xL and Mcl-1. Finally, Wit induces apoptosis, inhibits anchorage-dependent and -independent growth and invasion, and causes breast tumour regression in an ErbB2-driven transgenic mouse model.
These data warrant further development of Wit as a novel anticancer drug for targeting tumours that harbour hyperactivated STAT3 and STAT5.
STAT3 和 STAT5 与生长因子和细胞因子受体（如 EGFR 和 IL-6 受体 gp130）的结合对于它们的激活及其促进恶性转化的能力至关重要。因此，干扰这些生化过程可能会导致新型抗癌药物的发现。
采用免疫共沉淀、western blot、显微镜、DNA 结合、侵袭和软琼脂测定以及小鼠模型来研究天然产物 Withacnistin（Wit）抑制 STAT3/5 酪氨酸磷酸化和激活的机制。
Wit 阻断了 EGF 和 IL-6 刺激的 STAT3 和 STAT5 与 EGFR 和 gp130 的结合。Wit 抑制了 EGF、PDGF、IL-6、IFNβ 和 GM-CSF 刺激的 STAT3 和 STAT5 的酪氨酸磷酸化，但不抑制 EGFR 或 PDGFR。P-STAT3 和 P-STAT5 的抑制作用在 Wit 处理和生长因子刺激后数分钟内迅速发生。Wit 还抑制了 STAT3 核易位、DNA 结合、启动子转录激活，并抑制了 STAT3 靶基因如 Bcl-xL 和 Mcl-1 的表达水平。最后，Wit 诱导细胞凋亡，抑制锚定依赖性和非依赖性生长和侵袭，并导致 ErbB2 驱动的转基因小鼠模型中的乳腺肿瘤消退。
这些数据证明 Wit 作为一种新型抗癌药物具有进一步开发的潜力，可用于靶向 STAT3 和 STAT5 过度激活的肿瘤。
