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Pituitary Adenylate Cyclase-Activating Polypeptide Is a Potent Inhibitor of the Growth of Light Chain-Secreting Human Multiple Myeloma Cells

Department of Medicine, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana

Requests for reprints: Min Li, Section of Nephrology and Hypertension, Department of Medicine, School of Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-45, New Orleans, LA 70112-2632. Phone: 504-394-7199; Fax: 504-394-7169; E-mail: minlee{at}tulane.edu.

Multiple myeloma represents a malignant proliferation of plasma cells in the bone marrow, which often overproduces immunoglobulin light chains. We have shown previously that pituitary adenylate cyclase-activating polypeptide (PACAP) markedly suppresses the release of proinflammatory cytokines from light chain-stimulated human renal proximal tubule epithelial cells and prevents the resulting tubule cell injury. In this study, we have shown that PACAP suppresses the proliferation of human and light chain-secreting multiple myeloma–derived cells. The addition of PACAP suppressed light chain-producing myeloma cell–stimulated interleukin 6 (IL-6) secretion by the bone marrow stromal cells (BMSCs). A specific antagonist to either the human PACAP-specific receptor or the vasoactive intestinal peptide receptor attenuated the suppressive effect of PACAP on IL-6 production in the adhesion of human multiple myeloma cells to BMSCs. The secretion of IL-6 by BMSCs was completely inhibited by 10^–9 mol/L PACAP, which also attenuated the phosphorylation of both p42/44 and p38 mitogen-activated protein kinases (MAPK) as well as nuclear factor-B (NF-B) activation in response to the adhesion of multiple myeloma cells to BMSCs, whereas the inhibition of p42/44 MAPK signaling attenuated PACAP action. The signaling cascades involved in the inhibitory effect of PACAP on IL-6-mediated paracrine stimulation of light chain-secreting myeloma cell growth was mediated through the suppression of p38 MAPK as well as modulation of activation of transcription factor NF-B. These findings suggest that PACAP may be a new antitumor agent that directly suppresses light chain-secreting myeloma cell growth and indirectly affects tumor cell growth by modifying the bone marrow milieu of the multiple myeloma. (Cancer Res 2006; 66(17): 8796-803)

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				M. Li, K. S. Hering-Smith, E. E. Simon, and V. Batuman Myeloma light chains induce epithelial-mesenchymal transition in human renal proximal tubule epithelial cells Nephrol. Dial. Transplant., March 1, 2008; 23(3): 860 - 870. [Abstract] [Full Text] [PDF]