15-Deoxy- 12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF- B activity and down-regulation of antiapoptotic proteins

Cyclopentenone prostaglandins are potent inhibitors of nuclear factor– B (NFB), 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 NFB in the antineoplastic activity of the cyclopentenone prostaglandin 15-deoxy-PGJ2 (15d-PGJ2) in multiple myeloma (MM) and Burkitt lymphoma (BL) cells expressing constitutively active NFB. 15d-PGJ2 was found to suppress constitutive NFB activity and potently induce apoptosis in both types of B-cell malignancies. 15d-PGJ2–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). NFB inhibition is accompanied by rapid down-regulation of NFB–dependent antiapoptotic gene products, including cellular inhibitor-ofapoptosis protein 1 (cIAP-1), cIAP-2, Xchromosome-linked inhibitor-of-apoptosis protein (XIAP), and FLICE-inhibitory protein (cFLIP). These effects were mimicked by the proteasome inhibitor MG132, but not by the peroxisome proliferator-activated receptor(PPAR) agonist troglitazone, suggesting that 15d-PGJ2– induced apoptosis is independent of PPAR. Knockdown of the NFB p65subunit by lentiviral-mediated shRNA interference also resulted in apoptosis induction in malignant B cells with constitutively active NFB. The results indicate that inhibition of NFB plays a major role in the proapoptotic activity of 15d-PGJ2 in aggressive B-cell malignancies characterized by aberrant regulation of NFB. (Blood. 2005;105:1750-1758)