Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells

Abstract

B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated. Here, we show that rapamycin inhibited human soluble BAFF (hsBAFF)-induced cell proliferation and survival in normal and B-lymphoid (Raji and Daudi) cells by activation of PP2A and inactivation of Erk1/2. Pretreatment with PD98059, down-regulation of Erk1/2, expression of dominant negative MKK1, or overexpression of wild-type PP2A potentiated rapamycin's suppression of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1, inhibition of PP2A by okadaic acid, or expression of dominant negative PP2A attenuated the inhibitory effects of rapamycin. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR-T (mTOR-TE), conferred resistance to rapamycin's effects on PP2A, Erk1/2 and B-cell proliferation/viability, implying mTOR-dependent mechanism involved. The findings indicate that rapamycin inhibits BAFF-stimulated cell proliferation/survival by targeting mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Our data highlight that rapamycin may be exploited for preventing excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.

IL-2, IL-4, IFN-γ or TNF-α enhances BAFF-stimulated cell viability and survival by activating Erk1/2 and S6K1 pathways in neoplastic B-lymphoid cells

“…A series of data have uncovered that BAFF acts as a crucial factor in aggressive B-cell malignancies and various autoimmune diseases, such as SLE, RA and SS [13, 21, 41, 46, 47]. For example, lupus serum contains elevated levels of BAFF [48].…”

“…Our group has recently revealed that hsBAFF enhances cell proliferation/viability in Erk1/2-dependent manner in normal and neoplastic B-lymphoid cells [40, 41]. Moreover, hsBAFF also augments proliferation/survival in the cells, at least in part, through activating mTOR-mediated S6K1 and 4E-BP1 pathways [41, 42]. Here, we identified that IL-2, IL-4, IFN-γ or TNF-α reinforced hsBAFF-stimulated B-cell viability/survival by activating both Erk1/2 and S6K1 pathways.…”

Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

“…BAFF has been identified as a promoter of mTOR activation [33]. In B cells, rapamycin was able to block BAFF-stimulated mTOR activation, inhibit proliferation, and induce apoptosis [33, 34]. …”

Proteomic changes of CD4+/CD25+/forkhead box p3+ regulatory T cells in a 30‑day rat model of sepsis survival

“…Protein phosphatase 2A (PP2A) is a ubiquitous enzyme that promotes basal phosphatase activity to serve as a negative regulator of cell growth and division (51,52). The 14-3-3 family of highly conserved proteins bind to phosphorylated serine or threonine peptides to regulate cell growth and metabolic processes (53).…”