Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale de l'efatutazone, un agoniste du facteur de transcription PPARγ, pour le traitement d'un cancer épidermoïde de l'œsophage, seul ou en combinaison avec le cétuximab
The transcription factor PPARγ plays various roles in lipid metabolism, inflammation, cellular differentiation and apoptosis. PPARγ agonists used to treat hyperlipidemia may have utility in cancer treatment. Efatutazone is a novel later generation PPARγ agonist that selectively activates PPARγ target genes and has anti-proliferative effects in a range of malignancies. In this study, we investigated PPARγ status in esophageal squamous cell carcinoma (ESCC) and investigated the anti-proliferative effects of efatutazone. PPARγ was expressed heterogeneously in ESCC where it exhibited an inverse relationship with Ki-67 expression. PPARγ expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPARγ agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145, without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the MAPK pathway. Accordingly, the combination of efatutazone with the EGFR antibody cetuximab synergized to negatively regulate the PI3K-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC.