Gallium compound GaQ 3-induced Ca 2+ signalling triggers p53-dependent and -independent apoptosis in cancer cells

Rajan Gogna, Esha Madan, Bernhard Keppler, Uttam Pati

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)617-636
Number of pages20
JournalBritish Journal of Pharmacology
Volume166
Issue number2
DOIs
StatePublished - May 2012
Externally publishedYes

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Gallium
Reactive Oxygen Species
Apoptosis
Neoplasms
Clinical Trials, Phase I
Chromatin Immunoprecipitation
p53 Genes
Caspases
MicroRNAs
S Phase
Immunoprecipitation
Up-Regulation
Calcium
Cell Line
Messenger RNA
Membranes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Gallium compound GaQ 3-induced Ca 2+ signalling triggers p53-dependent and -independent apoptosis in cancer cells. / Gogna, Rajan; Madan, Esha; Keppler, Bernhard; Pati, Uttam.

In: British Journal of Pharmacology, Vol. 166, No. 2, 05.2012, p. 617-636.

Research output: Contribution to journalArticle

Gogna, Rajan ; Madan, Esha ; Keppler, Bernhard ; Pati, Uttam. / Gallium compound GaQ 3-induced Ca 2+ signalling triggers p53-dependent and -independent apoptosis in cancer cells. In: British Journal of Pharmacology. 2012 ; Vol. 166, No. 2. pp. 617-636.
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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.",
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