Journal article
NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma
Molecular cancer, Vol.9(1), pp.97-97
04/30/2010
DOI: 10.1186/1476-4598-9-97
PMCID: PMC2876994
PMID: 20433747
Abstract
Background: Myc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse Myc cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Emu enhancer. These mice, designated iMyc E mu, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc E mu mice, and an LBL-derived cell line, iMyc E mu-1.
Results: Nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc E mu mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc E mu-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-kappaB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-kappaB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc E mu-1 cells NF-kappaB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-kappaB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc E mu-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc E mu-1 cell proliferation and caused apoptosis, via downregulation of NF-kappaB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-kappaB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMyc E mu-1 cell proliferation, suggesting that these signaling pathways converge.
Conclusions: Our findings support the notion that constitutive activation of NF-kappaB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-kappaB, STAT3 and PI3K in the development of iMyc E mu B-cell lymphomas.
Details
- Title: Subtitle
- NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma
- Creators
- Seong-Su Han - University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA, USAHwakyung Yun - Hanseo University, Department of Biological Sciences, Choognam, South KoreaDong-Ju Son - University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA, USAVan S Tompkins - University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA, USALiangping Peng - University of Medicine and Dentistry of New Jersey, The Public Health Research Institute Center, Newark, NJ, USASeung-Tae Chung - National Institute of Toxicological Research, Korea Food and Dug Administration, Seoul, South KoreaJoong-Su Kim - Korea Research Institutes of Bioscience and Biotechnology, Daejeon, South KoreaEun-Sung Park - Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USASiegfried Janz - University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer, Vol.9(1), pp.97-97
- DOI
- 10.1186/1476-4598-9-97
- PMID
- 20433747
- PMCID
- PMC2876994
- NLM abbreviation
- Mol Cancer
- ISSN
- 1476-4598
- eISSN
- 1476-4598
- Publisher
- BioMed Central
- Language
- English
- Date published
- 04/30/2010
- Academic Unit
- Stead Family Department of Pediatrics; Pathology
- Record Identifier
- 9984083296302771
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