title: Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting.
abstract: Cisplatin is commonly recognized as a DNA-damaging drug; however, its versatile antitumor effects have been demonstrated to extend beyond this narrow functional attribute. The present study determined how cisplatin regulates alternative pathways and transcription factors to exert its additional antitumor actions. Cisplatin was observed to be able to trigger an endoplasmic reticulum stress response through aggravated nitrosative stress coupled to perturbed mitochondrial calcium (Ca2+) homeostasis, which substantially downregulated glucose-regulated protein (GRP) 78 expression by suppressing the cleavage of activating transcription factor (ATF) 6α (90 kDa) to its active 50 kDa subunit. Concomitantly, the ATF4-ATF3-C/emopamil binding protein homologous protein axis was activated by cisplatin, which triggered cellular glutathione (GSH) depletion by strongly inhibiting γ-glutamylcysteine synthetase heavy chain (γ-GCSh), a key enzyme in GSH biosynthesis. The present study also demonstrated that cisplatin substantially inhibited β-catenin, causing a marked downregulation of survivin and B-cell lymphoma (Bcl)-2. Taken together, the present results uncovered a novel mechanism of cisplatin that could simultaneously trigger the inhibition of three prominent antiapoptotic effector molecules (Bcl-2, survivin and GRP78) and effectively promote GSH depletion by inhibiting γ-GCSh. These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively.
authors.affiliation: Department of Neurosurgery, Chi-Mei Medical Center, Tainan 71004, Taiwan, R.O.C.; Department of Medical Research, Chi-Mei Medical Center, Tainan 71004, Taiwan, R.O.C.
authors.forename: Jinn-Rung
authors.initials: JR
authors.lastname: Kuo
authors.affiliation: Division of Clinical Pathology, Department of Pathology, National Defense Medical Center, Tri-Service General Hospital, Taipei 11490, Taiwan, R.O.C.
authors.forename: Hung-Sheng
authors.initials: HS
authors.lastname: Shang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Radiation Oncology, Tungs' Taichung Metro Harbor Hospital, Taichung 43503, Taiwan, R.O.C.
authors.forename: Kun-Goung
authors.initials: KG
authors.lastname: Lai
authors.affiliation: Translational Research Laboratory, Cancer Center, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
authors.forename: Tsan-Zon
authors.initials: TZ
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C.; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
authors.forename: Yin-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C.; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C.
authors.forename: Jeng-Fong
authors.initials: JF
authors.lastname: Chiou
keywords: Bcl-2; ER stress; GRP78; GSH depletion; cisplatin; survivin