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.

• Authors: Yasunori 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
• Journal: Blood (Blood) Vol. 111 Issue 10 Pg. 5118-29 (May 15 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18305221 (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)