Activation of Protein Kinase C δ Induces Growth Arrest in NPA Thyroid Cancer Cells Through Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase

Abstract

Protein kinase C (PKC) is a family of serine-threonine kinases that regulate many cell processes. To study the role of PKCδ in thyroid cancer cells, we used a replication-deficient adenovirus (PKCδAdV), to tightly control PKCδ expression. In NPA cells, activation of wild-type (WT) PKCδ with phorbol 12-myristate 13-acetate (PMA) induced an arrest in cell growth at G₁ phase, which was itself inhibited by the PKCδ inhibitor rottlerin. Furthermore, overexpression of a dominant negative PKCδ did not induce G₁ arrest. These findings strongly suggested that PKCδ induced cell growth arrest in NPA cells. We investigated the mechanism of G1 arrest by examining G₁-related proteins and mitogen-activated protein kinase (MAPK) by Western blotting. After activation of WTPKCδ 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 PKCδ induced cell growth arrest in NPA cells, through an ERK MAPK-p27^Kip1-cyclin E-pRb pathway. PKCδ may therefore be an effective molecular target for novel therapy in thyroid cancer.