Pioglitazone is an antidiabetic drug of the Thiazolidinediones (TZDs) class that acts as ligand for PPAR-γ, a member of peroxisome proliferator activated receptors (PPARs), that regulates lipid and glucose cell metabolism. Prior studies in in vitro and in vivo models of non-small cell lung cancer (NSCLC) showed that PPAR-γ modulation affects cancer cells proliferation and differentiation but few reported studies have investigated molecular pathways involved in the potential role of PPAR-γ agonists as anti-cancer agents.
NSCLC cell lines H460 and H1299, were treated with different doses of Pioglitazone. Anti-proliferative effect was determined by MTT, colony-forming assay and flow-cytometry. Protein expression was detected by Western Blot analysis while functional mitochondrial measurements were performed with SeaHorse© stress test. Finally, cell lines samples were analyzed with a cDNA microarray assay.
Pioglitazone significantly reduces cell proliferation and invasion with an IC50 of 1-5 µM. Analysis of apoptosis confirmed the data. Western blot analysis demonstrated a dose-related reduction of Survivin and phosphorylated proteins of MAP kinase pathway and cDNA microarray expression profiling showed a down-regulation of MAPK, Myc and RAS genes. Oxygen Consumption Rate (OCR) and proportional Glut-1 protein expression reduction of treated cells demonstrated cell bioenergetics modulation. Interestingly cDNA microarray analysis showed that also TGFβ pathway is regulated by Pioglitazione through pTGFβR1 and pSMAD3 down-regulation and consecutive up-regulation of total TGFβR1.
Pioglitazone regulates NSCLC cell lines proliferation and bioenergetics. Moreover, affecting TGFβ/SMAD signaling pathway, it could have a role in epitelial-to-mesenchymal transition (EMT) and cancer invasive phenotype development. These results encourage the study of PPAR-γ agonists as anti-cancer agents and promote research to explore the mechanisms beyond their activity in NSCLC models.
Clinical trial identification
Legal entity responsible for the study
Università degli Studi della Campania “Luigi Vanvitelli”.
Has not received any funding.
All authors have declared no conflicts of interest.