Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.
ABSTRACT Widespread use of L-type calcium channel blockers for treating hypertension has led to multiple epidemiologic studies to assess the risk of prostate cancer incidence. These studies revealed a reverse correlation between the likelihood of prostate cancer risk and the use of L-type calcium channel blockers among men without family history but the mechanism was not clear. In this study, we examined the expression profiles of multiple L-type calcium channel genes in prostate cancers and determined their functional roles in androgen receptor (AR) transactivation and cell growth. By reanalyzing the ONCOMINE database, we found that L-type calcium channel CACNA1D gene expression levels in cancer tissues were significantly higher than noncancer tissues in 14 of 15 published complementary deoxyribonucleic acid microarray data sets, of which 9 data sets showed an increase of 2- to 17-folds. Quantitative polymerase chain reaction and immunostaining experiments revealed that CACNA1D gene and its coding protein α1D were highly expressed in prostate cancers, especially in castration-resistant diseases, compared with benign prostate tissues. Consistent with the notion of CACNA1D as an ERG-regulated gene, CACNA1D gene expression levels were significantly higher in prostate cancers with TMPRSS2-ERG gene fusion compared with the cases without this gene fusion. Blocking L-type channel's function or knocking down CACNA1D gene expression significantly suppressed androgen-stimulated Ca(2+) influx, AR transactivation, and cell growth in prostate cancer cells. Taken together, these data suggest that CACNA1D gene overexpression is associated with prostate cancer progression and might play an important role in Ca(2+) influx, AR activation, and cell growth in prostate cancer cells.
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ABSTRACT: Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca2 + entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing the activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca2 + entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. An overexpression of TRPM7 significantly facilitated cholesterol dependent Ca2 + entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol-mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer.Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 01/2014; 1843(9):1839–1850. · 5.30 Impact Factor
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ABSTRACT: Previous studies have investigated differential gene expression in gastrointestinal (GI) epithelial cancers by microarray. The aim of the present study was to use data from the Oncomine database to identify genes that share a similar differential expression in two or more primary GI cancer sites.
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ABSTRACT: Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery.Cancer Cell International 04/2014; 14(1):34. DOI:10.1186/1475-2867-14-34 · 1.99 Impact Factor