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Carcinogenesis Advance Access published online on March 4, 2004
Carcinogenesis, doi:10.1093/carcin/bgh130
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CANCER BIOLOGY

Phosphorylation of FADD is critical for sensitivity to anticancer drug-induced apoptosis

Keiji Shimada 1, Syuichi Matsuyoshi 1, Mitsutoshi Nakamura 1, Eiwa Ishida 1, Munehiro Kishi 1, and Noboru Konishi 1*

1 Department of Pathology, Nara Medical University, Nara, 634-8521, Japan

* Corresponding author. E-mail: nkonishi{at}naramed-u.ac.jp.

Received 30 July 2003 ; revised 3 February 2004 ; accepted 20 February 2004

Abstract

FADD has been shown to be phosphorylated at serine 194 serine at the G2/M transition of the cell cycle. Here we investigated the contribution of this phosphorylation to apoptosis induced by anticancer drugs in two human prostate cancer cell lines, LNCaP and DU145. Both were arrested at G2/M and FADD was found to be phosphorylated at 194 serine on treatment with paclitaxel. Inhibition of paclitaxel-induced c-jun-NH2 terminal kinase (JNK) activation by treatment with a specific inhibitor, SP600125, or overexpression of a dominant negative mutant form of upstream kinases, MEK kinase 1 (MEKK1) and mitogen activated protein kinase kinase (MKK) 7, significantly reduced the increase of phosphorylated FADD. It is noteworthy that pretreatment with paclitaxel significantly upregulated MEKK1 expression, resulting in enhancement of etoposide- or cisplatin-induced MEKK1/MKK7-dependent JNK activation and apoptosis in LNCaP and DU145 cells. Interestingly, MEKK1 upregulation and the synergistic effects of paclitaxel on the anticancer drug-induced apoptosis were abolished by overexpression of mutant FADD (194 serine->alanine). The results clearly show that FADD phosphorylation at 194 serine affects functions both upstream and downstream of the MEKK1/MKK7/JNK1 pathway and is closely associated with chemosensitivity in prostate cancer cells. This is the first report indicating that phosphorylated FADD plays an essential role in the mechanisms of amplifications of chemotherapy-induced apoptosis.

FADD phosphorylation, MEKK1, c-jun NH2-terminal kinase, apoptosis, prostate cancer
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