title: Gallium compound GaQ(3) -induced Ca(2+)  signalling triggers p53-dependent and -independent apoptosis in cancer cells.
abstract: BACKGROUND AND PURPOSE A novel anti-neoplastic gallium complex GaQ(3)  (KP46), earlier developed by us, is currently in phase I clinical trial. GaQ(3)  induced S-phase arrest and apoptosis via caspase/PARP cleavage in a variety of cancers. However, the underlying mechanism of apoptosis is unknown. Here, we have explored the mechanism(s) of GaQ(3) -induced apoptosis in cancer cells, focusing on p53 and intracellular Ca(2+)  signalling. EXPERIMENTAL APPROACH GaQ(3) -induced cytotoxicity and apoptosis were determined in cancer cell lines, with different p53 status (p53(+/+) , p53(-/-)  and p53 mutant). Time course analysis of intracellular Ca(2+)  calcium release, p53 promoter activation, p53-nuclear/cytoplasmic movements and reactive oxygen species (ROS) were conducted. Ca(2+) -dependent formation of the p53-p300 transcriptional complex was analysed by co-immunoprecipitation and chromatin immunoprecipitation. Ca(2+)  signalling, p53, p300 and ROS were serially knocked down to study Ca(2+) -p53-ROS ineractions in GaQ(3) -induced apoptosis. KEY RESULTS GaQ(3)  triggered intracellular Ca(2+)  release stabilizing p53-p300 complex and recruited p53 to p53 promoter, leading to p53 mRNA and protein synthesis. p53 induced higher intracellular Ca(2+)  release and ROS followed by activation of p53 downstream genes including those for the micro RNA mir34a. In p53(-/-)  and p53 mutant cells, GaQ(3) -induced Ca(2+) -signalling generated ROS. ROS further increased membrane translocation of FAS and FAS-mediated extrinsic apoptosis. CONCLUSIONS AND IMPLICATIONS This study disclosed a novel mechanism of Ca(2+) -signalling-mediated p53 activation and ROS up-regulation. Understanding the mechanism of GaQ(3) -induced apoptosis will help establish this gallium-based organic compound as a potent anti-cancer drug.
authors.affiliation: Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Gogna
authors.forename: Esha
authors.initials: E
authors.lastname: Madan
authors.forename: Bernhard
authors.initials: B
authors.lastname: Keppler
authors.forename: Uttam
authors.initials: U
authors.lastname: Pati
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C408502:tris(8-quinolinolato)gallium (III); D015125:Oxyquinoline
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