Activation of protein kinase C delta induces growth arrest in NPA thyroid cancer cells through extracellular signal-regulated kinase mitogen-activated protein kinase.
Protein kinase C (PKC) is a family of serine-threonine kinases that regulate many cell processes. To study the role of PKCdelta in thyroid cancer cells, we used a replication-deficient adenovirus (PKCdeltaAdV), to tightly control PKCdelta expression. In NPA cells, activation of wild-type (WT) PKCdelta with phorbol 12-myristate 13-acetate (PMA) induced an arrest in cell growth at G(1) phase, which was itself inhibited by the PKCdelta inhibitor rottlerin. Furthermore, overexpression of a dominant negative PKCdelta did not induce G(1) arrest. These findings strongly suggested that PKCdelta induced cell growth arrest in NPA cells. We investigated the mechanism of G1 arrest by examining G(1)-related proteins and mitogen-activated protein kinase (MAPK) by Western blotting. After activation of WTPKCdelta with PMA, cyclin E expression and retinoblastoma protein (Rb) phosphorylation decreased; the expression of p27(Kip1) increased and the phosphorylation of extracellular signal-regulated kinase (ERK) MAPK decreased. These results indicated that the activation of PKCdelta induced cell growth arrest in NPA cells, through an ERK MAPK-p27(Kip1)-cyclin E-pRb pathway. PKCdelta may therefore be an effective molecular target for novel therapy in thyroid cancer.
Koike
Kenta
K
Department of Surgery, Kurume University School of Medicine, Fukuoka, Japan.
Fujii
Teruhiko
T
Nakamura
Anna M
AM
Yokoyama
Goro
G
Yamana
Hideaki
H
Kuwano
Michihiko
M
Shirouzu
Kazuo
K
D000256:Adenoviridae; D001943:Breast Neoplasms / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology; D002291:Carcinoma, Papillary / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051745:Protein Kinase C-delta / Q000096:biosynthesis / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000201:enzymology*; D014162:Transfection
D019927:Cyclin E; D005419:Flavonoids; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one