Hypoxia-induced down-modulation of PKCepsilon promotes trail-mediated apoptosis of tumor cells.
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.
Gobbi
Giuliana
G
Department of Human Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
Masselli
Elena
E
Micheloni
Cristina
C
Nouvenne
Antonio
A
Russo
Domenico
D
Santi
Patrizia
P
Matteucci
Alessandro
A
Cocco
Lucio
L
Vitale
Marco
M
Mirandola
Prisco
P
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D051744:Protein Kinase C-epsilon / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
C494811:BCL2L1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D051744:Protein Kinase C-epsilon