1. ¹Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510, Japan
2. ²Fourth Department of Internal Medicine, School of Medicine, Kitasato University, Kanagawa, Japan
3. ³Second Department of Pathology, School of Medicine, Toho University, Tokyo, Japan
4. ⁴Division of Pathology, Department of Cancer Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Correspondence: S Yamaoka, E-mail: shojmmb@tmd.ac.jp

Received 6 September 2004; Revised 24 January 2005; Accepted 24 January 2005; Published online 14 March 2005.

Abstract

Overexpression of CD30 and constitutive nuclear factor-B (NF-B) activation are hallmarks of the malignant Hodgkin Reed–Sternberg (H-RS) cells. Previous investigations have demonstrated that both proliferation and survival of H-RS cells require constitutive NF-B activity, which is comprised of the p50 and RelA subunits. We report here enhanced expression of NF-B2/p52 and RelB-containing NF-B DNA-binding activity in Epstein–Barr virus-negative H-RS cells. Kinetic studies revealed that a proteasome inhibitor MG132 induced p100 accumulation with reduced p52 expression in H-RS cells, suggesting proteasome-dependent processing of p100. In addition, treatment with a protein synthesis inhibitor cycloheximide rapidly downregulated inhibitor of NF-B (IB) kinase activity in H-RS cells. We also demonstrate that overexpression of CD30 in rat fibroblasts at levels comparable to those in H-RS cells results in constitutive IB kinase activation, proteasome-dependent p100 processing, and NF-B-dependent cell transformation. Our results thus indicate that CD30 triggers the noncanonical NF-B activation pathway, and suggest that deregulated CD30 signaling contributes to the neoplastic features of H-RS cells.