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
Authors: Linhui Gu
Qingqing Wang
Nan Li
Chunmei Wang
Haijun Zhong
Xuetao Cao
Ning Hui
Zhijian Cai
Shenglin Ma
Qinghua Zhang
Yunshan Yang
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: CaMKII; hCaMKIINbeta; ovarian cancer; cell growth; tumorigenicity
Affiliations: Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang, China.

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. 

Retracted: No

PubPeer comments:
 Brought to my attention by a reader. In Figure 6A, in the Actin panel, six of the bands look very similar to each other. The left-most band appears to have a sharp cutoff at its right-hand side, but otherwise, the six lanes show similar darker shading under the bands. Maybe the authors could take away any concerns by showing the original blot? ![file] , 
 I don t think these bands were duplicated. If you examin bands closely enough, you will find they are totally different, including darker shading under the bands. Please see figure below. ![file] , 
 2020 Expression of Concern. https: www.jbc.org content 295 26 8882 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 1 1 2021  VOLUME 284 (2009) PAGES 24773u201324782 This article has been withdrawn by the authors. The Journal raised questions regarding duplications in Fig. 2A and Fig. 6A. Fig. 2A: in the hCaMKIINu03b2 and u03b2-actin panels, the first two lanes corresponding to Marker and HeLa samples were duplicated. In addition, the HeLa sample lane on the hCaMKIINu03b2 panel and the CAOV-3 lane on the CaMKII panel were duplicated. The first, second, and fifth lanes on the fourth panel, CaMKII, were duplicated. Fig. 6A: in Cyclin A panel, lanes corresponding to pKIINu03b2 24 and 48 hr. samples were duplicated. In Cyclin B1 and D1 panels, lanes corresponding to Hu8910PM parental and pKIINb 72 hr. samples were duplicated. In Cyclin E, Cdk2 and Bax panels, lanes corresponding to 48 hr. pKIINu03b2 and 24 hr. mock samples were duplicated. In the actin panel, lanes corresponding to Hu8910PM parental; all mock samples, pKIINu03b2 48 hr., and pKIINu03b2 72 hr. were duplicated. The authors state that they disagree with the Journalu2019s findings. The authors state that this study was conducted more than 10 years ago. The age of the work and the lack of availability of data storage makes it difficult for the authors to retrieve the requested raw data. The authorsu2019 offer to replace the images in question with those from another experiment with the same conditions was declined by the Journal. The authors state that the above issues do not affect the interpretation of the data nor conclusions of this research study. This article reported the functional characterization of hCaMKIINu03b2, a novel molecule that the authors discovered. The authors state that the conclusions of this article have been confirmed by other independent studies. The authors have indicated that they plan to resubmit their findings elsewhere for publication. ,