Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a liga nd-activated transcription factor belonging to the steroid receptor superfa mily. It is a key regulator of adipogenic differentiation, the ligands of w hich have also been demonstrated to induce differentiation in human breast and colon cancer cell lines. This study examined PPAR gamma in non-small ce ll lung cancer (NSCLC). PPAR gamma mRNA and protein were expressed in NSCLC cell lines, with highest levels in adenocarcinomas. PPAR gamma protein was also expressed in 50% of primary lung cancers by immunohistochemistry. Tre atment of multiple cell lines with two distinct PPAR gamma Ligands in the p resence of serum resulted in growth arrest, irreversible loss of capacity f or anchorage-independent growth, decreased activity and expression of matri x metalloproteinase 2, and modulation of multiple markers in a manner consi stent with differentiation. Specifically, there was up-regulation of genera l markers of the differentiated state such as gelsolin, Mad, and p21. Down- regulation of specific markers of progenitor lineages for the peripheral lu ng, i.e., the type II pneumocyte lineage markers MUC1 and surfactant protei n-A and the Clara cell lineage marker CC10, also occurred. In addition, HTI 56, a marker of terminally differentiated type I pneumocytes, was also indu ced. Consistent with a more mature, less malignant phenotype, ligand treatm ent also inhibited the expression of cyclin D1 and led to hypophosphorylati on of the retinoblastoma protein. In contrast, in the absence of serum, lig and treatment rapidly resulted in apoptosis and substantially earlier onset of differentiation. Taken together, these results show that depending on t he growth milieu, ligands of PPAR gamma induce differentiation and apoptosi s in NSCLC, suggesting clinical utility for these agents.