Endogenous Human CaMKII Inhibitory Protein Suppresses Tumor Growth by Inducing Cell Cycle Arrest and Apoptosis through Down-regulation of the Phosphatidylinositide 3-Kinase/Akt/HDM2 Pathway

Abstract

Inhibition of calcium/calmodulin-dependent protein kinase II (CaMKII) results in hypophosphorylation of CaMKII substrates and in some cases suppresses cell growth. We previously presented the first report of the human CaMKII inhibitory protein, hCaMKIIN␤. Here we report the functional characterization of hCaMKIIN␤ in ovarian cancer cells. We showed that hCaMKIIN␤ was highly expressed in normal ovarian tissues but was not detected in human ovarian adenocarcinoma, indicating that decreased expression of hCaMKIIN␤ may be involved in the pathogenesis of human ovarian adenocarcinoma. As an endogenous CaMKII inhibitor, hCaMKIIN␤ could significantly inhibit the growth of human ovarian cancer cells in vitro. In vivo, hCaMKIIN␤ decreased the tumorigenicity and growth of HO-8910PM human ovarian cancer cells and prolonged the survival of tumor-bearing mice. hCaMKIIN␤ blocked cell cycle progression and induced apoptosis of HO-8910PM cells, which was correlated with the up-regulation of p21, p53, and Bax and the down-regulation of cyclin A, cyclin D1, cyclin E, CDK2, phosphorylated retinoblastoma, and Bcl-2. We further demonstrated that hCaMKIIN␤-mediated CaMKII inhibition suppressed Akt activation, leading to the down-regulation of HDM2, which was responsible for the up-regulation of p53 and p21 in human ovarian cancer cells. The tumor-suppressive effect and the negative expression in human ovarian cancer tissues suggest that hCaMKIIN␤ may play an important role in the regulation of tumor cell growth, possibly contributing to the development of new therapeutic strategies for ovarian cancer.Calcium/calmodulin-dependent protein kinase II (CaMKII) 3 is a multifunctional calcium/calmodulin-dependent serine/ threonine protein kinase. Recent studies suggest that CaMKII plays important roles in the control of cell cycle progression and cell proliferation (1-3). CaMKII inhibitors can inhibit CaMKII activity by interacting with the Ca 2ϩ

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

“…The endogenous CaM-KII inhibitor hCaMKIINa induces accumulation of p27 Kip1 , ERK dephosphorylation, and cell-cycle arrest in colorectal carcinoma (19). hCaMKIINa expression was negatively correlated with the severity of human colon adenocarcinoma, whereas hCaMKIINb expression was negatively correlated with the severity of ovarian adenocarcinoma (31). The analysis of hCaMKIINa expression in primary MTC revealed a broad variability.…”

The Multifunctional Ca2+/Calmodulin-dependent Kinase II δ (CaMKIIδ) Controls Neointima Formation after Carotid Ligation and Vascular Smooth Muscle Cell Proliferation through Cell Cycle Regulation by p21

“…We next sought to understand how CaMKII mechanistically promotes neointima growth. CaMKII controls various cell cycle regulators of the G1 phase (11,13). Therefore, we hypothesized that CaMKII␦ induces VSMC proliferation after carotid ligation through regulation of key cell cycle proteins.…”

“…Cell cycle arrest in response to CaMKII inhibition has been reported in both G1 (10,11) and in G2/M phase (7). Various effects of CAMKII inhibition on cell cycle progression have been reported in different models: decreased activity of cdk2 and 4 in NIH 3T3 cells (11), decreased phosphorylation and subsequent proteasomal degradation of the cell cycle inhibitor p27 in colon cancer cell lines (12) and up-regulation of the cell cycle inhibitor p21 with concomitant down-regulation of the positive regulators cyclin D1, cyclin E, and cdk2 in human ovarian cell lines (13).…”

The Metabotropic Glutamate Receptor Activates the Lipid Kinase PI3K in Drosophila Motor Neurons Through the Calcium/Calmodulin-Dependent Protein Kinase II and the Nonreceptor Tyrosine Protein Kinase DFak

“…Although the ability of CaMKII to activate PI3K has only recently been reported (Ma et al 2009), it has been well established in mammals that CaMKII phosphorylates both Fak and Pyk2 on multiple serines on the C terminus. These phosphorylation events can activate Pyk2 by enabling subsequent tyrosine phosphorylations (particularly at Tyr402) via mechanisms that are incompletely understood (Della Rocca et al 1997;Soltoff 1998;Zwick et al 1999;Heidinger et al 2002;Fan et al 2005;Montiel et al 2007).…”

“…Although the possibility that CaMKII can activate PI3K has only recently been reported (Ma et al 2009), altered CaMKII activity alters certain motor neuron phenotypes in Drosophila in a manner similar to altered PI3K activity (Griffith et al 1994;Park et al 2002). One way that CaMKII activity can be altered is by expression of the constitutively active CaMKII T287D : this variant is rendered active even in the absence of calcium or calmodulin by the phosphomimetic T287D substitution in the autophosphorylation site (Fong et al 1989).…”