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Overexpressed NF-kappaB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells.

Abstract
The nuclear factor-kappaB (NF-kappaB) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-kappaB is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-kappaB-inducing kinase (NIK) is overexpressed at the pretranslational level in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells (H-RS) that do not express viral regulatory proteins. The overexpression of NIK causes cell transformation in rat fibroblasts, which is abolished by a super-repressor form of IkappaBalpha. Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-kappaB and NF-kappaB-dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/gammac(null) mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-kappaB activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.
AuthorsYasunori Saitoh, Norio Yamamoto, M Zahidunnabi Dewan, Haruyo Sugimoto, Vicente J Martinez Bruyn, Yuki Iwasaki, Katsuyoshi Matsubara, Xiaohua Qi, Tatsuya Saitoh, Issei Imoto, Johji Inazawa, Atae Utsunomiya, Toshiki Watanabe, Takao Masuda, Naoki Yamamoto, Shoji Yamaoka
JournalBlood (Blood) Vol. 111 Issue 10 Pg. 5118-29 (May 15 2008) ISSN: 1528-0020 [Electronic] United States
PMID18305221 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • RNA, Small Interfering
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase
Topics
  • Animals
  • Cell Transformation, Neoplastic
  • Gene Expression Regulation, Neoplastic
  • Hodgkin Disease (etiology, pathology)
  • Leukemia-Lymphoma, Adult T-Cell (etiology, pathology)
  • Mice
  • NF-kappa B (antagonists & inhibitors)
  • Protein-Serine-Threonine Kinases (genetics, physiology)
  • RNA, Small Interfering (pharmacology)
  • Rats
  • Reed-Sternberg Cells (enzymology, pathology)

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