NF-kappaB/STAT3/PI3K signaling crosstalk in iMyc E mu B lymphoma. Mol Cancer 2010 Apr 30;9:97
Date
05/04/2010Pubmed ID
20433747Pubmed Central ID
PMC2876994DOI
10.1186/1476-4598-9-97Scopus ID
2-s2.0-77951566551 (requires institutional sign-in at Scopus site) 97 CitationsAbstract
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.
Author List
Han SS, Yun H, Son DJ, Tompkins VS, Peng L, Chung ST, Kim JS, Park ES, Janz SAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Blotting, Western
Cell Line, Tumor
DNA Fragmentation
Disease Models, Animal
Electrophoretic Mobility Shift Assay
Enhancer Elements, Genetic
Enzyme Activation
Enzyme-Linked Immunosorbent Assay
Gene Expression
Gene Expression Regulation, Neoplastic
Genes, Immunoglobulin Heavy Chain
Genes, myc
Immunoprecipitation
Lymphoma, B-Cell
Mice
NF-kappa B
Phosphatidylinositol 3-Kinases
Receptor Cross-Talk
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor
Signal Transduction
