Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 124, Issue 11, Pages 2607-2615Publisher
WILEY
DOI: 10.1002/ijc.24257
Keywords
Aurora A; Aurora kinase inhibitor; HTLV-1; ATL; CHFR
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [19591122]
- Foundation for Promotion of Cancer Research in Japan, Uehara Memorial Foundation, Public Trust Haraguchi Memorial Cancer Research Fund, Takeda Science Foundation, Japan Leukemia Research Fund
- Princes Takamatsu Cancer Research Fund [07-23905]
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Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia (ATL). Aurora A, a mitotic checkpoint protein, is overexpressed in human cancer cells. The cell cycle-dependent turnover of Aurora A is regulated by E3 ubiquitin ligases such as checkpoint with fork head-associated and ring finger (CHFR). Here, we found overexpression of Aurora A protein in HTLV-1-infected T-cell lines and primary ATL cells. The expression of CHFR mRNA was reduced in these cells by abnormal methylation of CHFR promoter region. Knockdown of Aurora A using small interfering RNA suppressed the growth of HTLV-1-infected T-cell line. Transfection of Aurora A expression plasmid enhanced Tax-induced nuclear factor-kappa B (NF-kappa B) reporter activity. Transfection of CHFR expression plasmid into an HTLV-1-infected T-cell line reduced cell growth, Aurora A protein level and constitutive NF-kappa B reporter activity. Aurora kinase inhibitor suppressed the growth and survival of HTLV-1-infected T-cell lines and primary ATL cells. It also reduced constitutive NF-kappa B activity in an HTLV-1-infected T-cell line by reducing I kappa B kinase beta phosphorylation and the expression or antiapoptotic protein survivin. Our results suggested that loss of CHFR expression resulted to accumulation of Aurora A, which increased NF-kappa B activity. These findings highlight the critical role of Aurora A in HTLV-1-infected T cells, making this molecule a potentially suitable target for future therapies for ATL. (C) 2009 Wiley-Liss, Inc.
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