Abstract
Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell death accompanied by down-regulation of IGF-1, ErbB2, and VEGF downstream kinases PI3K/AKT, as well as the MEK/ERK-mediated signaling pathways. Conversely, knockdown of CAMK2N1 had a significant opposite effects on these phenotypes. Our analyses suggest that CAMK2N1 plays a tumor suppressive role in prostate cancer cells. Reduced CAMK2N1 expression correlates to human prostate cancer progression and predicts poor clinical outcome, indicating that CAMK2N1 may serve as a biomarker. The inhibition of tumor growth by expressing CAMK2N1 established a role of CAMK2N1 as a therapeutic target.
Highlights
Prostate cancer is one of the most common malignancies among men and the second most common cause of male cancer-related deaths [1]
Our findings revealed a tumor suppressive role for CAMK2N1 and established CAMK2N1 as molecular determinant in hormone sensitivity of prostate cancer
We analyzed the abundance of CAMK2N1 mRNA in prostate cancer tissues compared to matched normal-like control from same patient (n = 10) by quantitative RT-PCR analysis
Summary
Prostate cancer is one of the most common malignancies among men and the second most common cause of male cancer-related deaths [1]. CaMKII signaling plays a role in cell-cycle progression by activating MEK/ERK to enhance the phosphorylation of p27Kip1[8]. CAMK2N1-mediated inhibition of CaMKII activity regulates the cell-cycle progression in colon cancer cells through de-activation of MEK/ERK kinase activity and p27 protein accumulation
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