A Novel PPARɣ Ligand, PPZ023, Overcomes Radioresistance Via ER Stress and Cell Death in Human Non-small-cell Lung Cancer Cells

Peroxisome proliferator-activated receptor gamma (PPARɣ) agonists exert powerful anticancer effects by suppressing tumor growth. In this study, we developed PPZ023 (1-(2-(ethylthio)benzyl)-4-(2-methoxyphenyl)piperazine), a novel PPAR ligand candidate, and investigated the underlying signaling pathways in both non-small-cell lung cancer (NSCLC) and radio-resistant NSCLC cells. To identify whether PPZ023 has anticancer effects in NSCLC and radioresistant NSCLC cells, we performed WST-1, LDH, Western blot, and caspase-3 and -9 activity assays. Furthermore, we isolated exosomes from PPZ023-treated NSCLC cells and studied cell death signaling. PPZ023 reduces cell viability and increases LDH cytotoxicity and caspase-3 activity in NSCLC cells. PPZ023 induces cell death by generating reactive oxygen species (ROS) and triggering mitochondrial cytochrome c release. PPZ023 treatment causes cell death via the PERK-eIF2α-CHOP axis in both NSCLC cell lysates and exosomes, and PERK and CHOP knockdown significantly blocks ER stress-mediated apoptosis by reducing cleaved caspase-3. Interestingly, diphenyleneiodonium (DPI, a Nox inhibitor) inhibits PPZ023-induced cell death via ER stress, and PPARɣ knockdown inhibits PPZ023-induced ROS, ER stress, and cell death. Moreover, PPZ023, in combination with radiation, causes synergic cell death via exosomal ER stress in radioresistant NSCLC cells, indicating that PPZ023/radiation overcomes radioresistance. Taken together, our results suggest that PPZ023 is a powerful anticancer reagent for overcoming radioresistance.