15-deoxy-delta(12-14)-prostaglandin-j2 and Burkitt-Lymphoma

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