Abstract
Multiple myeloma (MM) is an incurable B-cell malignancy, characterized by the proliferation of malignant plasma cells. B-cell-activating factor (BAFF, also known as BlyS or B-lymphocyte stimulator) and a proliferation-inducing ligand (APRIL), the two members of the tumor necrosis factor ligand superfamily, enhance the production of antibodies and regulate and promote proliferation and survival. Both BAFF and APRIL have an important role in B cell lymphoma and chronic lymphocytic leukemia cell survival. This study evaluates the expression of BAFF, APRIL, and their three receptors in two human MM cell lines (KM3 and PRMI 8226) and ten primary MM cell lines, and their effects on the growth of MM cells in vivo. MM cells were found to express BAFF, APRIL, and their three receptor genes both at the gene and protein levels. ELISA found high concentrations of BAFF and APRIL in the supernatants of these cultured cells. Treatment with PS-341 decreased the concentration of BAFF and APRIL. The WST-1 analysis of growth found that BAFF and APRIL stimulated the proliferation of MM cells. PS-341 inhibited this enhanced proliferation and induced apoptosis. Making use of the rhTACI-Fc to block the BAFF- and APRIL-induced activation of NF-κB2, we demonstrated that the NF-κB2-p52/RelB signal contributes to MM cell survival. In summary, PS-341 was shown to block this pathway. PS-341 inhibits the autocrine secretion of BAFF and APRIL and thereby MM cell proliferation by the alterative NF-κB2 pathway. BAFF and APRIL appear to be the targets of PS-341.
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References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA CancerJ Clin. 2005;55:74–108. doi:10.3322/canjclin.55.2.74.
Attal M, Harousseau J, Stoppa A, Sotto J, Fuzibet J, Rossi J, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. New Engl J Med. 1996;335:91–7. doi:10.1056/NEJM199607113350204.
Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962–72. doi:10.1182/blood-2007-10-078022.
Guan ZB, Shui Y, Zhang SQ. Two related ligands of the TNF family, BAFF and APRIL, in rabbit: molecular cloning, 3D modeling, and tissue distribution. Cytokine. 2007;39:192–200. doi:10.1016/j.cyto.2007.07.190.
Knight AK, Radigan L, Marron T, Langs A, Zhang L. Cunningham-Rundles C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol. 2007;124:182–9. doi:10.1016/j.clim.2007.04.012.
Mackay F, Silveira PA, Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol. 2007;19:327–36. doi:10.1016/j.coi.2007.04.008.
Zheng Y, Gallucci S, Gaughan JP, Gross JA, Monestier M. A role for B cell-activating factor of the TNF family in chemically induced autoimmunity. J Immunol. 2005;175:6163–8.
Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57. doi:10.1182/blood-2003-06-1984.
Adams J. Proteasome inhibition in cancer: development of PS-341. Semin Oncol. 2001;28:613–9. doi:10.1016/S0093-7754(01)90034-X.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood. 2003;101:1530–4. doi:10.1182/blood-2002-08-2543.
Tan C, Waldmann TA. Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia. Cancer Res. 2002;62:1083–6.
Boulanger E, Meignin V, Oksenhendler E. Bortezomib (PS-341) in patients with human herpesvirus 8-associated primary effusion lymphoma. Br J Haematol. 2008;141:559–61. doi:10.1111/j.1365-2141.2008.07057.x.
Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB, et al. The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene. 2003;22:4953–63. doi:10.1038/sj.onc.1206656.
Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9:1136–44.
Liu J, Li J, Su C, Huang B, Luo S. Soluble Fms-like tyrosine kinase-1 expression inhibits the growth of multiple myeloma in nude mice. Acta Biochim Biophys Sin (Shanghai). 2007;39:499–506. doi:10.1111/j.1745-7270.2007.00310.x.
Endo T, Nishio M, Enzler T, Cottam HB, Fukuda T, James DF, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-{kappa}B pathway. Blood. 2007;109:703–10. doi:10.1182/blood-2006-06-027755.
Chu VT, Enghard P, Riemekasten G, Berek C. In vitro and in vivo activation induces BAFF and APRIL expression in B cells. J Immunol. 2007;179:5947–57.
Acknowledgment
This study was supported by a grant from the Nature Science Program Foundation of Guangdong Province (No. 06021319). We thank Pro. HouJiang for providing us with MM cell line KM3.
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Li, W., Li, J., Su, C. et al. New targets of PS-341: BAFF and APRIL. Med Oncol 27, 439–445 (2010). https://doi.org/10.1007/s12032-009-9230-z
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DOI: https://doi.org/10.1007/s12032-009-9230-z