Gallium compound GaQ3-induced Ca2+signalling triggers p53-dependent and -independent apoptosis in cancer cells
- Author(s)
- Rajan Gogna, Esha Madan, Bernhard Keppler, Uttam Pati
- Abstract
BACKGROUND AND PURPOSE A novel anti-neoplastic gallium complex GaQ3 (KP46), earlier developed by us, is currently in phase I clinical trial. GaQ3 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 GaQ3-induced apoptosis in cancer cells, focusing on p53 and intracellular Ca2+ signalling. EXPERIMENTAL APPROACH GaQ3-induced cytotoxicity and apoptosis were determined in cancer cell lines, with different p53 status (p53+/+, p53-/-and p53 mutant). Time course analysis of intracellular Ca2+ calcium release, p53 promoter activation, p53-nuclear/ cytoplasmic movements and reactive oxygen species (ROS) were conducted. Ca2+-dependent formation of the p53-p300 transcriptional complex was analysed by co-immunoprecipitation and chromatin immunoprecipitation. Ca2+ signalling, p53, p300 and ROS were serially knocked down to study Ca2+-p53-ROS ineractions in GaQ3-induced apoptosis. KEY RESULTS GaQ3 triggered intracellular Ca2+ release stabilizing p53-p300 complex and recruited p53 to p53 promoter, leading to p53 mRNA and protein synthesis. p53 induced higher intracellular Ca2+ release and ROS followed by activation of p53 downstream genes including those for the micro RNA mir34a. In p53-/-and p53 mutant cells, GaQ3-induced Ca2+-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 Ca2+-signalling-mediated p53 activation and ROS up-regulation. Understanding the mechanism of GaQ3-induced apoptosis will help establish this gallium-based organic compound as a potent anti-cancer drug.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Jawaharlal Nehru University
- Journal
- British Journal of Pharmacology
- Volume
- 166
- Pages
- 617-636
- No. of pages
- 20
- ISSN
- 0007-1188
- DOI
- https://doi.org/10.1111/j.1476-5381.2011.01780.x
- Publication date
- 2012
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301206 Pharmacology, 104003 Inorganic chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/7e3964c3-9001-4e23-99ec-b3f51367e157