Interleukin-2 induces NF-kappaB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells

• Published in: The Journal of pathology 2010-06, Vol.221 (2), p.164-174
• Main Authors: Chan, Ka-Kui, Shen, Lijun, Au, Wing-Yan, Yuen, Hiu-Fung, Wong, Kai-Yau, Guo, Tianhuan, Wong, Michelle Ly, Shimizu, Norio, Tsuchiyama, Junjiro, Kwong, Yok-Lam, Liang, Raymond Hs, Srivastava, Gopesh
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; B-Cell CLL-Lymphoma 10 Protein; Cell Line; Cell Nucleus - metabolism; Gene Expression Regulation - genetics; Humans; Interleukin-2 - pharmacology; Interleukin-2 - physiology; Lymphoma, Extranodal NK-T-Cell - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - genetics; Transcription Factors - metabolism
• ISSN: 1096-9896
• DOI: 10.1002/path.2699

Deregulation of nuclear factor (NF)-kappaB signalling is common in cancers and is essential for tumourigenesis. Constitutive NF-kappaB activation in extranodal natural killer (NK)-cell lymphoma, nasal type (ENKL) is known to be associated with aberrant nuclear translocation of BCL10. Here we investigated the mechanisms leading to NF-kappaB activation and BCL10 nuclear localization in ENKLs. Given that ENKLs are dependent on T-cell-derived interleukin-2 (IL2) for cytotoxicity and proliferation, we investigated whether IL2 modulates NF-kappaB activation and BCL10 subcellular localization in ENKLs. In the present study, IL2-activated NK lymphoma cells were found to induce NF-kappaB activation via the PI3K/Akt pathway, leading to an increase in the entry of G(2)/M phase and concomitant transcription of NF-kappaB-responsive genes. We also found that BCL10, a key mediator of NF-kappaB signalling, participates in the cytokine receptor-induced activation of NF-kappaB. Knockdown of BCL10 expression resulted in deficient NF-kappaB signalling, whereas Akt activation was unaffected. Our results suggest that BCL10 plays a role downstream of Akt in the IL2-triggered NF-kappaB signalling pathway. Moreover, the addition of IL2 to NK cells led to aberrant nuclear translocation of BCL10, which is a pathological feature of ENKLs. We further show that BCL10 can bind to BCL3, a transcriptional co-activator and nuclear protein. Up-regulation of BCL3 expression was observed in response to IL2. Similar to BCL10, the expression and nuclear translocation of BCL3 were induced by IL2 in an Akt-dependent manner. The nuclear translocation of BCL10 was also dependent on BCL3 because silencing BCL3 by RNA interference abrogated this translocation. We identified a critical role for BCL10 in the cytokine receptor-induced NF-kappaB signalling pathway, which is essential for NK cell activation. We also revealed the underlying mechanism that controls BCL10 nuclear translocation in NK cells. Our findings provide insight into a molecular network within the NF-kappaB signalling pathway that promotes the pathogenesis of NK cell lymphomas.