Journal article

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

Y Hirokawa, M Arnold, H Nakajima, J Zalcberg, H Maruta

Cancer Biology & Therapy | TAYLOR & FRANCIS INC | Published : 2005

Abstract

PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for both neurofibromatosis (NF) and RAS transformation in vivo. FK228, a histone deacetylase (HDAC) inhibitor, activates a very specific set of genes such as the tumor suppressor WAF1, an inhibitor of cyclin-dependent kinases (CDKs), and suppresses the growth of these tumors. In addition, this drug downregulates cyclin D1, which is upregulated by RAS through PAK1, in breast cancers. In this study, we demonstrate that FK228 at 0.1-1 nM significantly reduces the kinase activity of PAK1 in these cells, without affecting the protein level of PAK1. Interestingly, estrogen receptor (ER) and PAK1 mutually activate each other in breast cancers...

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