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PloS one
2019;14 (4): e0214847.

Impact of p53 status on TRAIL-mediated apoptotic and non-apoptotic signaling in cancer cells.

Anna Willms, Hella Schittek, Sascha Rahn, Justyna Sosna, Ufuk Mert, Dieter Adam, Anna Trauzold
Author Information
  1. Anna Willms: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
  2. Hella Schittek: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
  3. Sascha Rahn: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
  4. Justyna Sosna: Institute of Immunology, University of Kiel, Kiel, Germany. ORCID
  5. Ufuk Mert: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany.
  6. Dieter Adam: Institute of Immunology, University of Kiel, Kiel, Germany.
  7. Anna Trauzold: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University of Kiel, Kiel, Germany. ORCID
PMID: 30947287 DOI: 10.1371/journal.pone.0214847

Abstract

Due to their ability to preferentially induce cell death in tumor cells, while sparing healthy cells, TNF-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL-R1 or anti-TRAIL-R2-specific antibodies are under clinical investigations for cancer-treatment. However, TRAIL-Rs may also induce signaling pathways, which result in malignant progression. TRAIL receptors are transcriptionally upregulated via wild-type p53 following radio- or chemotherapy. Nevertheless, the impact of p53 status on the expression and signaling of TRAIL-Rs is not fully understood. Therefore, we analyzed side by side apoptotic and non-apoptotic signaling induced by TRAIL or the agonistic TRAIL-R-specific antibodies Mapatumumab (anti-TRAIL-R1) and Lexatumumab (anti-TRAIL-R2) in the two isogenic colon carcinoma cell lines HCT116 p53+/+ and p53-/-. We found that HCT116 p53+/+ cells were significantly more sensitive to TRAIL-R-triggering than p53-/- cells. Similarly, A549 lung cancer cells expressing wild-type p53 were more sensitive to TRAIL-R-mediated cell death than their derivatives with knockdown of p53. Our data demonstrate that the contribution of p53 in regulating TRAIL-R-induced apoptosis does not correlate to the levels of TRAIL-Rs at the plasma membrane, but rather to p53-mediated upregulation of Bax, favouring the mitochondrial amplification loop. Consistently, stronger caspase-9 and caspase-3 activation as well as PARP-cleavage was observed following TRAIL-R-triggering in HCT116 p53+/+ compared to HCT116 p53-/- cells. Interestingly, HCT116 p53+/+ cells showed also a more potent activation of non-canonical TRAIL-R-induced signal transduction pathways like JNK, p38 and ERK1/ERK2 than p53-/- cells. Likewise, these cells induced IL-8 expression in response to TRAIL, Mapatumumab or Lexatumumab significantly stronger than p53-/- cells. We obtained similar results in A549 cells with or without p53-knockdown and in the two isogenic colon cancer cell lines RKO p53+/+ and p53-/-. In both cellular systems, we could clearly demonstrate the potentiating effects of p53 on TRAIL-R-mediated IL-8 induction. In conclusion, we found that wild-type p53 increases TRAIL-R-mediated apoptosis but simultaneously augments non-apoptotic signaling.

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MeSH Term

A549 Cells
Apoptosis
Cell Membrane
Gene Knockdown Techniques
Genes, p53
HCT116 Cells
Humans
Interleukin-8
Neoplasms
Receptor Activator of Nuclear Factor-kappa B
Receptors, TNF-Related Apoptosis-Inducing Ligand
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand
Tumor Suppressor Protein p53
bcl-2-Associated X Protein

Chemicals

BAX protein, human
CXCL8 protein, human
Interleukin-8
Receptor Activator of Nuclear Factor-kappa B
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
TNFRSF10B protein, human
TNFRSF11A protein, human
TNFSF10 protein, human
TP53 protein, human
Tumor Suppressor Protein p53
bcl-2-Associated X Protein
Journal Article Research Support, Non-U.S. Gov't

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