Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells

Giuliana Gobbi, Elena Masselli, Cristina Micheloni, Antonio Nouvenne, Domenico Russo, Patrizia Santi, Alessandro Matteucci, Lucio Cocco, Marco Vitale, Prisco Mirandola

Research output: Contribution to journalArticle

Abstract

Tumor oxygen status is considered as a prognostic marker that impacts on malignant progression and outcome of tumor therapy. TNF-related apoptosis inducing ligand (TRAIL) plays a key role in cancer immunity, with potential applications in cancer therapy. Protein kinase C (PKC)ε, a transforming oncogene, has a role in the protection of cardiomyocytes and neurons from hypoxia-induced damage while, it can also modulate the susceptibility of tumor cells to TRAIL-induced cell death. Here we demonstrate that hypoxia induces a tumor cell phenotype highly sensitive to the cytotoxic effects of TRAIL. Based on the observation that: i) PKCε expression levels are impaired during hypoxia, ii) the overexpression of PKCε, but not of a kinase-inactive PKCε mutant, is able to revert the hypoxia-induced sensitivity to TRAIL, iii) the down-modulation of PKCε levels by RNA interference, on the contrary, induces the highly TRAIL-sensitive phenotype, iv) the inhibition of hypoxia-inducible transcription factor-1α (HIF-1α) by specific siRNA blocks both the hypoxia-induced down-modulation of PKCε and the induction of the highly TRAIL-sensitive phenotype; we conclude that the HIF-1α upregulation during hypoxia is associated to PKCε down-modulation that likely represents the key molecular event promoting the apoptogenic effects of TRAIL in hypoxic tumor cells.

Original languageEnglish
Pages (from-to)719-729
Number of pages11
JournalInternational Journal of Oncology
Volume37
Issue number3
DOIs
Publication statusPublished - Sep 2010

Fingerprint

TNF-Related Apoptosis-Inducing Ligand
Protein Kinase C
Apoptosis
Neoplasms
Hypoxia-Inducible Factor 1
Phenotype
Transcription Factors
RNA Interference
Hypoxia
Oncogenes
Cardiac Myocytes
Small Interfering RNA
Immunity
Cell Death
Up-Regulation
Oxygen
Therapeutics

Keywords

  • Apoptosis
  • Bcl-xL
  • HIF-1α
  • Hypoxia
  • PKCε
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gobbi, G., Masselli, E., Micheloni, C., Nouvenne, A., Russo, D., Santi, P., ... Mirandola, P. (2010). Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells. International Journal of Oncology, 37(3), 719-729. https://doi.org/10.3892/ijo-00000721

Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells. / Gobbi, Giuliana; Masselli, Elena; Micheloni, Cristina; Nouvenne, Antonio; Russo, Domenico; Santi, Patrizia; Matteucci, Alessandro; Cocco, Lucio; Vitale, Marco; Mirandola, Prisco.

In: International Journal of Oncology, Vol. 37, No. 3, 09.2010, p. 719-729.

Research output: Contribution to journalArticle

Gobbi, G, Masselli, E, Micheloni, C, Nouvenne, A, Russo, D, Santi, P, Matteucci, A, Cocco, L, Vitale, M & Mirandola, P 2010, 'Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells', International Journal of Oncology, vol. 37, no. 3, pp. 719-729. https://doi.org/10.3892/ijo-00000721
Gobbi, Giuliana ; Masselli, Elena ; Micheloni, Cristina ; Nouvenne, Antonio ; Russo, Domenico ; Santi, Patrizia ; Matteucci, Alessandro ; Cocco, Lucio ; Vitale, Marco ; Mirandola, Prisco. / Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells. In: International Journal of Oncology. 2010 ; Vol. 37, No. 3. pp. 719-729.
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