Protein kinase C‐delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis

• Published in: British journal of haematology 2003-06, Vol.121 (6), p.849-856
• Main Authors: Ni, Hongyu, Ergin, Melek, Tibudan, Shalini S., Denning, Mitch F., Izban, Keith F., Alkan, Serhan
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Apoptosis - drug effects; Benzopyrans - pharmacology; Biological and medical sciences; Blotting, Western; Down-Regulation; Enzyme Inhibitors - pharmacology; Hematology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Medical sciences; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; myeloma; PKC; Protein Kinase C - metabolism; Protein Kinase C-delta; rottlerin; safingol; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Tumor Cells, Cultured
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.2003.04368.x

The growth and proliferation of multiple myeloma (MM) cells are influenced by various cytokines produced by bone marrow stromal cells. As cytokine interaction between malignant plasma cells and neighbouring stromal cells is important in the pathogenesis of MM, the understanding of intracellular signalling events elicited by this interaction is of central importance. Recent reports have shown that protein kinase C (PKC) is directly involved in modulating apoptosis in different cells types, including those of haematopoietic neoplasms. In the present study, we analysed the expression patterns of PKC isoforms in the myeloma cell lines U266, RPMI‐8226 and K620. This analysis demonstrated common expression of PKC‐δ, PKC‐ι, PKC‐µ and PKC‐ζ in all three myeloma cell lines. PKC‐δ expression in plasma cells from 11 patients with MM was also shown by immunohistochemistry, utilizing a monoclonal mouse anti‐human PKC‐δ antibody. U266 cells treated with the broad PKC inhibitor safingol (l‐threo‐dihydrosphingosine) or the PKC‐δ‐specific inhibitor rottlerin (3′‐[(8‐Cinnamoyl‐5,7‐dihydroxy‐2,2‐dimethyl‐2H‐1‐benzopyran‐6‐yl)methyl]‐2′,4′,6′‐trihydroxy‐5′‐methylacetophenone) showed decreased PKC‐δ in the particulate fraction and resulted in significant apoptosis. Primary myeloma cells also showed apoptosis after treatment with the PKC inhibitors, as detected by both flow cytometric and morphological evaluation. Our results indicate that PKC‐δ is commonly expressed in myeloma cells and plays an important role in plasma cell survival.