PPARgamma and Agonists against Cancer: Rational Design of Complementation Treatments

Abstract

PPARgamma is a member of the ligand-activated nuclear receptor superfamily: its ligands act as insulin sensitizers and some are approved for the treatment of metabolic disorders in humans. PPARgamma has pleiotropic effects on survival and proliferation of multiple cell types, including cancer cells, and is now subject of intensive preclinical cancer research. Studies of the recent decade highlighted PPARgamma role as a potential modulator of angiogenesis in vitro and in vivo. These observations provide an additional facet to the PPARgamma image as potential anticancer drug. Currently PPARgamma is regarded as an important target for the therapies against angiogenesis-dependent pathological states including cancer and vascular complications of diabetes. Some of the studies, however, identify pro-angiogenic and tumor-promoting effects of PPARgamma and its ligands pointing out the need for further studies. Below, we summarize current knowledge of PPARgamma regulatory mechanisms and molecular targets, and discuss ways to maximize the beneficial activity of the PPARgamma agonists.

Figure 1

PPARγ structure and regulation. (a) Schematic representation of the domain structure of the PPARγ-1 and PPARγ-2. The mutations associated with metabolic syndrome are indicated. LF: loss of function; GF: gain of function. (b) Positive and negative regulators of the PPARγ gene transcription. (c) The regulation of PPARγ levels by Rb and E2F. (d) The mechanism of ligand-dependent PPARγ activation. (e) The regulation of PPARγ activity by MEK and Erk kinases: MEK1 activates Erk-1/2, which phosphorylates PPARγ and targets it to proteasomes; in addition, MEK1 binds PPARγ in the nucleus and exports it to the cytoplasm. MEK5 can serve as coactivator for the PPARγ.

Figure 2

Mechanisms of transrepression by PPARγ. (a) Ligand-independent repression: preferential recruitment of corepressors in the absence of agonists. (b) Direct binding and sequestration of transcription factors on example of NFκB. (c) Activation of genes encoding inhibitors of transcription factor (e.g., NFκB inhibitor, IκBα). (d) Direct binding and inactivation of kinases, which activate transcription factors (e.g., the blockade of JNK activation of cJun). (e) Competitive binding of the coactivator complex. (f) The blockade of corepressor clearance: sumoylated PPARγ stabilizes corepressor complexes (NCoR, Tab2, and TBL1) on the promoter and facilitates the recruitment of HDAC3. In the absence of sumoylation, NCoR, Tab2, and TBL1 are subject to ubiquitination and proteasomal clearance.

Figure 3

PPARγ effects in cancer cells. (a) The induction of Cdk inhibitor, p27 causes growth arrest due to reduced MCM7 activity and subsequent blockade of replication. (b) The induction of GADD45 impairs Cyclin B and causes G2M growth arrest. In addition, the activation of JNK and p38 kinases via MEKK4 initiates cell death by apoptosis. (c) PPARγ activation by hormones and nutrition in normal cells and by agonists in cancer cells may activate the differentiation programs.

Figure 4

PPARγ effects on the endothelial, pericytic, tumor and immune cells in the tumor microenvironment: the consequences of angiogenesis and possible ways to augment antitumor actions. Pro-angiogenic and tumor-promoting events are shown in red. The opposing effects are in blue. The proposed drugs are shown in black. (a) Summary of the PPARγ molecular effects in the endothelial cells. TEM, transendothelial migration. (b) PPARγ molecular effects on the VSMCs. (c) The effects on macrophages and tumor cells.