Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

Figure 3

PPAR $\gamma$ agonists inhibit Stat3-mediated IL-6 gene expression in myeloma cells. Inactivation of IL-6-activated Stat3 by PPAR$\gamma$ agonists occurs in a PPAR$\gamma$-dependent manner; however, the molecular mechanisms by which two distinct PPAR$\gamma$ agonists (15d-PGJ₂ and troglitazone) suppress IL-6-activated Stat3 in MM cells differ as shown in (a) [211]. Direct complex formation between phosphorylated Stat3 and PPAR$\gamma$ 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$\gamma$ transcription factor to DNA in the promoter region and, thus, can occur in the absence of a PPRE. However troglitazone activated PPAR$\gamma$ promotes redistribution of the corepressor SMRT from PPAR$\gamma$ to phosphorylated Stat3 so that Stat3 can no longer recruit the transcriptional machinery necessary for gene expression ((a), right) [211]. High levels of IL-6 are found in MM and promote myeloma cell proliferation and survival and indirectly promote tumor-associated angiogenesis. The PPAR$\gamma$ agonists troglitazone and 15d-PGJ₂ have been shown to inhibit transcription of the IL-6 promoter driven by C/EBPβ and NF-κB [212]. Troglitazone-activated PPAR$\gamma$ 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$\gamma$ 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$\gamma$-mediated inhibition of IL-6 gene expression occurs in response to 15d-PGJ₂. Although 15d-PGJ₂-activated PPAR$\gamma$ inhibits C/EBPβ-mediated transactivation of the IL-6 promoter similarly to troglitazone-activated PPAR$\gamma$, the predominant mode of inhibition is through 15d-PGJ₂-activated PPAR$\gamma$ 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$\gamma$ activation ((b), right). The schematics in this figure were adapted from [211, 212].

(a)

(b)