Anticancer Role of PPAR Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes
PPAR agonists inhibit Stat3-mediated IL-6 gene expression in myeloma cells. Inactivation of IL-6-activated Stat3 by PPAR agonists occurs in a PPAR-dependent manner; however, the molecular mechanisms by which two distinct PPAR agonists (15d-PGJ2 and troglitazone) suppress IL-6-activated Stat3 in MM cells differ as shown in (a) . Direct complex formation between phosphorylated Stat3 and PPAR activated by 15d-PGJ2 prevents Stat3 binding to its cognate response element (SBE) on the promoters of target genes ((a), left). This mode of transcriptional inactivation does not require binding of the activated PPAR transcription factor to DNA in the promoter region and, thus, can occur in the absence of a PPRE. However troglitazone activated PPAR promotes redistribution of the corepressor SMRT from PPAR to phosphorylated Stat3 so that Stat3 can no longer recruit the transcriptional machinery necessary for gene expression ((a), right) . High levels of IL-6 are found in MM and promote myeloma cell proliferation and survival and indirectly promote tumor-associated angiogenesis. The PPAR agonists troglitazone and 15d-PGJ2 have been shown to inhibit transcription of the IL-6 promoter driven by C/EBPβ and NF-κB . Troglitazone-activated PPAR binds to C/EBPβ preventing binding to its cognate response element on the IL-6 promoter, which is the major mechanistic pathway of troglitazone-mediated downregulation of IL-6 expression. In addition activated PPAR competes with NF-κB for the PGC-1 coactivator, which leads to decreased NF-κB binding to the κB response element on the IL-6 promoter contributing to inhibition of IL-6 gene expression, albeit to a lesser extent than inhibition of C/EBPβ ((b), left). A slightly different mechanistic emphasis on PPAR-mediated inhibition of IL-6 gene expression occurs in response to 15d-PGJ2. Although 15d-PGJ2-activated PPAR inhibits C/EBPβ-mediated transactivation of the IL-6 promoter similarly to troglitazone-activated PPAR, the predominant mode of inhibition is through 15d-PGJ2-activated PPAR using the coactivator PGC-1 as a bridging protein to interact with NF-κB to prevent transactivation of the IL-6 promoter. Furthermore, 15d-PGJ2 inactivates NF-κB by inhibiting phosphorylation of IKK and IκB independently of PPAR activation ((b), right). The schematics in this figure were adapted from [211, 212].