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, hCaMKIINbeta. Here we report the functional characterization of hCaMKIINbeta in ovarian cancer cells. We showed that hCaMKIINbeta was highly expressed in normal ovarian tissues but was not detected in human ovarian adenocarcinoma, indicating that decreased expression of hCaMKIINbeta may be involved in the pathogenesis of human ovarian adenocarcinoma. As an endogenous CaMKII inhibitor, hCaMKIINbeta could significantly inhibit the growth of human ovarian cancer cells in vitro. In vivo, hCaMKIINbeta decreased the tumorigenicity and growth of HO-8910PM human ovarian cancer cells and prolonged the survival of tumor-bearing mice. hCaMKIINbeta 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 hCaMKIINbeta-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 hCaMKIINbeta may play an important role in the regulation of tumor cell growth, possibly contributing to the development of new therapeutic strategies for ovarian cancer.
Highlights
Strates and in presented the sfoirmTsthericesapasoerrsttisocuflpetphhreeahsssuebmseacenenllCwgarMiotwhKtdIhIr.aiWnwhenibpibrtoeyvrtyiohpuersolay-uthtpohlarrsye.soTnimhinepeoJporrtuoantrentianrlokrleiansiasisened.tRhqeeuceceonsnttitosrtonulsdoirefescgseaulrlgdcgiyencsgtlethpartogCraeMssiKoInI tein, hCaMKdIuINplic. aHteiorenws einreFpigo.rt2tAheafnudncFtiigo.n6alAc.hFairga.c2teAr:izian- theanhdCaceMllKpIIrNolβifearnadtioβn-a(c1t–in3)p. aCnaeMlsK, ItIheinfhiribsittors can inhibit tion of hCaMtwKoIIlNaneisncoovrarreiasnpocanndcienrgcteollsM
We showed that hCaMKIIN was preferentially expressed in normal human ovarian tissues, but its expression was decreased in human ovarian cancer tissues
In vitro kinase assay based on substrate phosphorylation by calmodulin-dependent protein kinase II (CaMKII) showed that CaMKII kinase activity was significantly suppressed by the recombinant hCaMKIIN protein, GST-KIIN, in a dose-dependent manner (Fig. 1B)
Summary
Strates and in presented the sfoirmTsthericesapasoerrsttisocuflpetphhreeahsssuebmseacenenllCwgarMiotwhKtdIhIr.aiWnwhenibpibrtoeyvrtyiohpuersolay-uthtpohlarrsye.soTnimhinepeoJporrtuoantrentianrlokrleiansiasisened.tRhqeeuceceonsnttitosrtonulsdoirefescgseaulrlgdcgiyencsgtlethpartogCraeMssiKoInI tein, hCaMKdIuINplic. aHteiorenws einreFpigo.rt2tAheafnudncFtiigo.n6alAc.hFairga.c2teAr:izian- theanhdCaceMllKpIIrNolβifearnadtioβn-a(c1t–in3)p. aCnaeMlsK, ItIheinfhiribsittors can inhibit tion of hCaMtwKoIIlNaneisncoovrarreiasnpocanndcienrgcteollsM. We demonstrated that hCaMKIIN could significantly inhibit the growth of human ovarian cancer cells via blocking cell cycle progression and inducing apoptosis. Negative HO-8910PM human ovarian cancer cells were transfected with hCaMKIIN expression vector (pKIIN) or mock vector (supplemental Fig. S1A).
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