APRIL binding to BCMA activates a JNK2-FOXO3-GADD45 pathway and induces a G2/M cell growth arrest in liver cells.
The TNF superfamily ligands APRIL and BAFF bind with different affinity to two receptors, BCMA and TACI, and induce cell survival and/or proliferation, whereas BAFF also binds specifically to BAFFR. These molecules were considered specific for the immune system. Recently, however, they were also found in epithelial and mesenchymal noncancerous and cancerous tissues and cell lines. In this article, we report that hepatocellular carcinoma (HCC) cell lines HepG2 and Hep3B and HCC specimens express APRIL and BAFF and their receptors BCMA and BAFFR, but not TACI; APRIL/BCMA is enhanced in HCC, compared with normal liver tissue. In contrast to previous reports, APRIL binding to BCMA decreases cell proliferation by inducing G(2)/M cell cycle arrest, whereas BAFF has no effect on cell growth. HCC cells therefore represent a rare system in which these two ligands (APRIL and BAFF) exert a differential effect and may serve as a model for specific APRIL/BCMA actions. We show that the effect of APRIL is mediated via BCMA, which does not activate the classical NF-κB pathway, whereas it induces a novel signaling pathway, which involves JNK2 phosphorylation, FOXO3A activation, and GADD45 transcription. In addition, JNK2 mediates the phosphorylation of Akt, which is activated but does not participate in the antiproliferative effect of APRIL. Furthermore, transcriptome analysis revealed that APRIL modifies genes specifically related to cell cycle modulation, including MCM2/4/5/6, CDC6, PCNA, and POLE2. Our data, therefore, identify a novel APRIL/BCMA signaling pathway in HCC and suggest that APRIL could have a pleiotropic role in tumor biology.
Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion, GR-71003, Greece.
George
G
Notas
Vassilia-Ismini
VI
Alexaki
Marilena
M
Kampa
Vassiliki
V
Pelekanou
Ioannis
I
Charalampopoulos
Sanaa
S
Sabour-Alaoui
Iosif
I
Pediaditakis
Valérie
V
Dessirier
Achille
A
Gravanis
Efstathios N
EN
Stathopoulos
Andreas
A
Tsapis
Elias
E
Castanas
D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology / Q000276:immunology*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology*; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D000097642:GADD45 Proteins
D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D048688:MAP Kinase Kinase 7; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; C499517:FOXO3 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C118660:PDS5B protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; C482569:MAP2K7 protein, human