Atypical protein kinase C zeta as a target for chemosensitization of tumor cells.
Exposure of tumor cells to cytotoxic agents simultaneously activates a variety of intracellular signaling pathways. Some of these pathways involve enzymes from the protein kinase C (PKC) family of serine/threonine kinases. This family includes isoenzymes that negatively influence cell death, whereas other demonstrate an opposite effect. The present study analyzes the role of the zeta atypical PKC isoform in tumor cell response to cytotoxic agents. Using a histone H1 phosphorylation assay, we showed that both tumor necrosis factor alpha and etoposide activate PKCzeta in U937 human leukemic cells. Stable transfection of a kinase-dead, dominant-negative PKCzeta mutant in U937 cells decreases Bcl-2 expression while increasing the expression of Bax and several procaspases. This transfection also prevents etoposide-induced nuclear factor-kappaB nuclear translocation and accumulation of X-linked inhibitor of apoptosis protein. PKCzeta inhibition accelerates the occurrence of apoptosis in leukemic cells exposed to etoposide and tumor necrosis factor alpha. This sensitization was confirmed in vitro by use of a clonogenic assay. In addition, PKCzeta inhibition sensitized tumor cells grown in nude mice to etoposide. These results indicate that PKCzeta isoform is a protective signals that is activated in tumor cells exposed to a cytotoxic agent. This inducible resistance factor thus appears an attractive target for chemosensitization of tumor cells.
Filomenko
Rodolphe
R
INSERM U517, EPHE, Ecole Pratique des Hautes Etudes, IFR, Institut Féderatif de Recherche 100, Faculties of Medicine & Pharmacy, 21000 Dijon, France.
Poirson-Bichat
Florence
F
Billerey
Claire
C
Belon
Jean-Paul
JP
Garrido
Carmen
C
Solary
Eric
E
Bettaieb
Ali
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D019073:HT29 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D009154:Mutation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D000099221:Protein Kinase C zeta
D000970:Antineoplastic Agents; D005047:Etoposide; D011493:Protein Kinase C; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta