PPARγ and MEK Interactions in Cancer

الملخص EN

Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity.

Two synthetic PPARγ 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, PPARγ 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 PPARγ 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).

PPARγ ligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling.

In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγ with MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.