Inhibitory Effect Of A Novel CaMKII Inhibitory Protein HCaMKIINα On Tumor Growth And Cell Cycle Progression And The Underlying Mechanisms

CaMKâ…¡is critical for many physiological and pathological functions including celldifferentiation and growth. CaMKâ…¡inhibitors can block CaMKâ…¡activity by connectingCa²⁺/CaM binding site or affecting its catalytic function to cause cell growth inhibition byimpairment of cell cycle progression or induction of apoptosis in a variety of malignantcells. Up to now, four endogenous CaMKâ…¡inhibitory proteins (CaMKâ…¡Ns) have beenidentified: two rat brain-derived CaMKâ…¡N, rCaMKâ…¡Nβand rCaMKâ…¡Nα, and two humanCaMKâ…¡N, hCaMKâ…¡Nβand hCaMKâ…¡Nα, hCaMKâ…¡Nαwas identified as CaMKâ…¡inhibitory protein from human bone marrow stromal cells by us in 2002. Our previousstudy showed that hCaMKâ…¡Nαinduced cell cycle arrest at S phase with the increasing inthe expression of p27 protein. In this study, we investigated the mechanisms of theinhibitory effects of hCaMKâ…¡Nα-mediated CaMKâ…¡inhibition on the growth and cell cycleprogression of tumor cells. Our findings provide a new mechanistic model for thecross-talk between CaMKâ…¡and MAPK signaling which converges in MEK/ERK activity,leading to the phosphorylation and the degradation of p27, thus promoting the cell cycleprogression. In addition hCaMKâ…¡Nαmight also inhibit immune escape of tumors bysuppressing the release of immunosuppressive factors such as VEGF and IL-8. Therefore,hCaMKâ…¡Nα-mediated CaMKâ…¡inhibition supresses tumor growth, representing apotemtial manner to control colon cancer development.