APRIL Binding to BCMA Activates a JNK2–FOXO3–GADD45 Pathway and Induces a G2/M Cell Growth Arrest in Liver Cells

Abstract

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 G2/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.

BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis

“…BAFF, APRIL, and their receptors (BAFFR, BCMA and TACI) in addition to their well-established role in the B-lymphocyte network [19]–[22] have also been identified in an array of normal and neoplastic cell lines [14], [23]–[29] and tissues [30]–[36] of various origin. In previous reports, we identified an active role of these molecules in normal and pathological non-hemopoietic tissues [13], [30], [34], [37], as well as in pluripotent adult mesenchymal cells [30]. Through NFκB activation and newly identified signaling cascades [13], [29], these molecules are involved in cell cycle arrest and blockade of cell proliferation.…”

“…APRIL binds with high affinity to BCMA and TACI, while BAFF, sharing a lower affinity interaction with these two receptors, binds mainly to BAFFR (reviewed in [11]. Binding to their cognate receptors triggers diverse signaling pathways, involving, Nuclear Factor kappa-B (NFκB), and/or mitogen-activated kinases [12], [13]. These pathways have also been reported to participate in the evolution of glial cell tumors [14].…”

Gadd45 in Stress Signaling, Cell Cycle Control, and Apoptosis

“…The TNF superfamily ligand APRIL also induces Gadd45 transcription. Binding of APRIL to the receptor BCMA triggers JNK2 phosphorylation, FOXO3A activation, and Gadd45 transcription inhibiting cell proliferation in hepatocellular carcinoma cells through cell cycle arrest in the G 2 /M (Notas et al 2012 ).…”

APRIL, BCMA and TACI proteins are abnormally expressed in non-small cell lung cancer

“…The initial data demonstrated that APRIL is overexpressed in leukemia and lymphoma, and promotes tumorigenesis, while later reports indicated a role for this cytokine beyond hematopoietic malignancies (11,19–24). …”

“…It binds to and BCMA, two members of the TNF receptor family. APRIL has been observed to be highly expressed in several tumor tissues, where it stimulates the growth of solid tumor cells (9) and promotes their development and progression (10,11). Whether APRIL and its receptors BCMA and TACI serve roles in development of NSCLC is still not known.…”