PPAR gamma and MEK Interactions in Cancer

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPAR gamma ligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPAR gamma and its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPAR gamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPAR gamma ligands themselves activate the ERK cascade through nongenomic and often PPAR gamma-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPAR gamma with MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients. Copyright (C) 2008 E. Burgermeister and R. Seger.