글로벌 연구동향
방사선생물학
- 2020년 12월호
[Exp Mol Med.] A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cellsKIRAMS / 김태우, 홍성희*
- 출처
- Exp Mol Med.
- 등재일
- 2020 Oct
- 저널이슈번호
- 52(10):1730-1743. doi: 10.1038/s12276-020-00511-9. Epub 2020 Oct 12.
- 내용
Abstract
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.Affiliations
Tae Woo Kim 1 , Da-Won Hong 1 , Chang-Mo Kang 1 , Sung Hee Hong 2
1 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Korea.
2 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Korea. gobrian@kcch.re.kr.
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