15-deoxy-delta(12-14)-prostaglandin-j2 and Multiple-Myeloma

Cyclopentenone prostaglandins are potent inhibitors of nuclear factor-kappa B (NF-kappa B), a transcription factor with a critical role in promoting inflammation and connected with multiple aspects of oncogenesis and cancer cell survival. In the present report, we investigated the role of NF-kappa B in the antineoplastic activity of the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in multiple myeloma (MM) and Burkitt lymphoma (BL) cells expressing constitutively active NF-kappa B. 15d-PGJ(2) was found to suppress constitutive NF-kappa B activity and potently induce apoptosis in both types of B-cell malignancies. 15d-PGJ(2)-induced apoptosis occurs through multiple caspase activation pathways involving caspase-8 and caspase-9, and is prevented by pretreatment with the pan-caspase inhibitor ZVAD (z-Val-Ala-Asp). NF-kappa B inhibition is accompanied by rapid down-regulation of NF-kappa B-dependent antiapoptotic gene products, including cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), and FLICE-inhibitory protein (cFLIP). These effects were mimicked by the proteasome inhibitor MG-132, but not by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist troglitazone, suggesting that 15d-PGJ(2)-induced apoptosis is independent of PPAR-gamma. Knockdown of the NF-kappa B p65-subunit by lentiviral-mediated shRNA interference also resulted in apoptosis induction in malignant B cells with constitutively active NF-kappa B. The results indicate that inhibition of NF-kappa B plays a major role in the proapoptotic activity of 15d-PGJ(2) in aggressive B-cell malignancies characterized by aberrant regulation of NF-kappa B.

Topics: Apoptosis; B-Lymphocyte Subsets; bcl-X Protein; Burkitt Lymphoma; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases; Cell Line; Cell Line, Tumor; DNA-Binding Proteins; Down-Regulation; Enzyme Activation; Growth Inhibitors; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; K562 Cells; Multiple Myeloma; NF-kappa B; Prostaglandin D2; Proteins; Proto-Oncogene Proteins c-bcl-2; X-Linked Inhibitor of Apoptosis Protein

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.

Topics: Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Enzyme Activation; Humans; Immunohistochemistry; Immunologic Factors; In Situ Nick-End Labeling; Interleukin-6; Ligands; Membrane Potentials; Mitochondria; Multiple Myeloma; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Tretinoin