title: Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells.
abstract: KRAS mutant lung cancers have long been considered as untreatable with drugs. Transforming growth factor-β-activated kinase 1 (TAK1) appears to play an anti-apoptotic role in response to multiple stresses and has been reported to be a responsive kinase that regulates cell survival in KRAS-dependent cells. In this study, in order to find a useful approach to treat KRAS mutant lung cancer, we focused on the combined effects of 5Z-7-oxozeaenol, a TAK1 inhibitor, with hyperthermia (HT) in KRAS mutant lung cancer cell line A549. Annexin V-FITC/PI assay, cell cycle analysis, and colony formation assay revealed a significant enhancement in apoptosis induced by HT treatment, when the cells were pre-incubated with 5Z-7-oxozeaenol in a dose-dependent manner. The enhanced apoptosis by 5Z-7-oxozeaenol was accompanied by a significant increase in reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). In addition, western blot showed that 5Z-7-oxozeaenol enhanced HT-induced expressions of cleaved caspase-3, cleaved caspase-8, and HSP70 and decreased HT-induced expressions of Bcl-2, p-p38, p-JNK, and LC3. Moreover, 5Z-7-oxozeaenol pre-treatment resulted in a marked elevation of intracellular calcium level which might be associated with endoplasmic reticulum (ER) stress-related pathway. Taken together, our data provides further insights of the mechanism of action of 5Z-7-oxozeaenol and HT treatment, and their potential application as a novel approache to treat patients with KRAS mutant lung cancer.
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan. zhao@med.u-toyama.ac.jp.
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Zhao
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Paras
authors.initials: P
authors.lastname: Jawaid
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Mati Ur
authors.initials: MU
authors.lastname: Rehman
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D003131:Combined Modality Therapy; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms / Q000628:therapy*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D000970:Antineoplastic Agents; D020930:MAP Kinase Kinase Kinases; D017382:Reactive Oxygen Species; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols
keywords: 5Z-7-oxozeaenol; Apoptosis; Calcium; Hyperthermia; Mitochondria; TAK1