Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance.
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. Here we provide an evidence suggesting that breast cancers require PAK1 for their estrogen-dependent growth. Moreover, the treatment with FK228 strongly inhibits the estrogen-dependent growth of human breast cancers (both tamoxifen-sensitive and resistant cell lines) in vivo, suggesting that FK228 and other anti-PAK1 drugs would be useful for the treatment of breast cancers which become resistant to currently used estrogen antagonists such as tamoxifen.
Hirokawa
Yumiko
Y
Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.
Arnold
Melissa
M
Nakajima
Hidenori
H
Zalcberg
John
J
Maruta
Hiroshi
H
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D054462:p21-Activated Kinases
D018931:Antineoplastic Agents, Hormonal; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D013629:Tamoxifen; C087123:romidepsin; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases