title: ICAM-1 and AMPK regulate cell detachment and apoptosis by N-methyl-N'-nitro-N-nitrosoguanidine, a widely spread environmental chemical, in human hormone-refractory prostate cancers.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, plays a crucial role in the regulation of DNA repair. PARP-1 hyperactivation causes DNA damage and cell death. The underlying mechanism is complicated and is through diverse pathways. The understanding of responsible signaling pathways may offer implications for effective therapies. After concentration-response determination of N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG, a PARP-1 activating agent and an environmental mutagen) in human hormone-refractory prostate cancers, the data showed that concentrations below 5μM did not change cell survival but cause a time-dependent up-regulation of intracellular adhesion molecule-1 (ICAM-1) in mRNA, total protein and cell surface levels. Detection of phosphorylation and degradation of IκB-α and nuclear translocation of NF-κB showed that MNNG induced the activation of NF-κB that was responsible for the ICAM-1 up-regulation since PDTC (a NF-κB inhibitor) significantly abolished this effect. However, higher concentrations (e.g., 10μM) of MNNG induced a 61% detachment of the cells which were apoptosis associated with the activation of AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Further identification showed that both AMPK and JNK other than p38 MAPK functionally contributed to cell death. The remaining 39% attached cells were survival associated with high ICAM-1 expression. In conclusion, the data suggest that NF-κB-dependent up-regulation of ICAM-1 plays a key role on cell attachment and survival; whereas, activation of AMPK and JNK participates in cytotoxic signaling pathways in detached cells caused by PARP-1 activation.
authors: School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan.
authors: Yi-Cheng
authors: YC
authors: Chen
authors: Pin-Hsuan
authors: PH
authors: Lu
authors: Jui-Ling
authors: JL
authors: Hsu
authors: Chia-Chun
authors: CC
authors: Yu
authors: Jih-Hwa
authors: JH
authors: Guh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000008:administration & dosage / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D008769:Methylnitronitrosoguanidine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases