http://www.cnr.it/ontology/cnr/individuo/prodotto/ID27771

Hypoxia-induced down-modulation of PKCepsilon promotes trail-mediated apoptosis of tumor cells. (Articolo in rivista)

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Hypoxia-induced down-modulation of PKCepsilon promotes trail-mediated apoptosis of tumor cells. (Articolo in rivista) (literal)

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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 PKCepsilon promotes trail-mediated apoptosis of tumor cells.
in International journal of oncology
(literal)

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Gobbi G, Masselli E, Micheloni C, Nouvenne A, Russo D, Santi P, Matteucci A, Cocco L, Vitale M, Mirandola P. (literal)

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Department of Human Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma Center for Morphology and Body Composition (CMBC), University of Parma; Department of Clinical Sciences, University of Parma, Ospedale Maggiore, Via Gramsci 14, 43126 Parma; Stem Cell Transplantation Unit, Department of Haematology, University of Brescia, Piazzale Spedali Civili 1, Brescia; Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, Via Irnerio 48; IGM-CNR, Bologna Unit c/o I.O.R., Bologna, Italy (literal)

Titolo

Hypoxia-induced down-modulation of PKCepsilon promotes trail-mediated apoptosis of tumor cells. (literal)

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)epsilon, 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) PKCepsilon expression levels are impaired during hypoxia, ii) the overexpression of PKCepsilon, but not of a kinase-inactive PKCepsilon mutant, is able to revert the hypoxia-induced sensitivity to TRAIL, iii) the down-modulation of PKCepsilon levels by RNA interference, on the contrary, induces the highly TRAIL-sensitive phenotype, iv) the inhibition of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) by specific siRNA blocks both the hypoxia-induced down-modulation of PKCepsilon and the induction of the highly TRAIL-sensitive phenotype; we conclude that the HIF-1alpha upregulation during hypoxia is associated to PKCepsilon down-modulation that likely represents the key molecular event promoting the apoptogenic effects of TRAIL in hypoxic tumor cells. (literal)

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