Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance.

摘要: PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for both neurofibromatosis (NF) and RAS transformation in vivo. FK228, histone deacetylase (HDAC) inhibitor, activates very specific set of genes such as the tumor suppressor WAF1, an inhibitor cyclin-dependent kinases (CDKs), suppresses growth these tumors. In addition, this drug downregulates cyclin D1, which upregulated by through breast cancers. study, we demonstrate that FK228 at 0.1-1 nM significantly reduces kinase activity PAK1 cells, without affecting protein level PAK1. Interestingly, estrogen receptor (ER) mutually activate each other Here provide evidence suggesting cancers require their estrogen-dependent growth. Moreover, treatment with strongly inhibits human (both tamoxifen-sensitive resistant cell lines) vivo, anti-PAK1 drugs would be useful become to currently used antagonists tamoxifen.