Synergistic Effects of PPAR𝛾 Ligands and Retinoids in Cancer Treatment

Figure 3

A hypothetical schematic representation of the synergistic anticancer effects of the combination of PPAR ligands plus other agents. When PPARs are activated by ligand binding, they are able to heterodimerize with RXR and activate the target gene expression by binding to the PPRE element. Therefore, the retinoids which bind to RXR may be the most preferable partner for the PPAR agonists (A). However, in some types of cancers, the MAPK pathway phosphorylates RXRα, and the accumulated nonfunctional p-RXRα interferes with the function of the remaining normal RXRα, thereby promoting the growth of cancer cells. The activation of RTKs by their specific ligands (growth factors) can play a critical role in the stimulation of the MAPK pathway. Therefore, the agents which target the activation of RTKs (B) and/or the MAPK pathway (C) restore the function of RXRα as a master regulator of nuclear receptors in cancer cells and this will support the synergistic growth inhibition by PPAR and RXR ligands in cancer cells. The HDACs enforce a tight chromatin structure and thereby repress the transcription of target genes controlled by PPAR/RXR. Therefore, the combination of a PPAR agonist plus an HDAC inhibitor is more efficient to inhibit the growth of cancer cells (D). Finally, the conventional chemotherapeutic agents also cause synergistic or enhancing effects to inhibit cancer cell growth by the combination of PPAR ligands (E). L: ligand.