Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.
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.
Department of Urology, The University of Kansas Medical Center, Kansas City, KS; Department of Urology, Tongji Hospital, Huanzhong University of Science & Technology, Wuhan, China.
Ruibao
R
Chen
Department of Urology, The University of Kansas Medical Center, Kansas City, KS; Department of Urology, Tongji Hospital, Huanzhong University of Science & Technology, Wuhan, China.
Xing
X
Zeng
Department of Urology, The University of Kansas Medical Center, Kansas City, KS; Department of Anatomy and Pharmacology, Three Gorges University College of Medicine, Yichang, China.
Ruitao
R
Zhang
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
Jiaoti
J
Huang
Department of Urology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, China.
Xiangxing
X
Kuang
Department of Urology, Tongji Hospital, Huanzhong University of Science & Technology, Wuhan, China.
Jun
J
Yang
Department of Urology, Tongji Hospital, Huanzhong University of Science & Technology, Wuhan, China.
Jihong
J
Liu
Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS.
Ossama
O
Tawfik
Department of Urology, The University of Kansas Medical Center, Kansas City, KS.
James Brantley
JB
Thrasher
Department of Urology, The University of Kansas Medical Center, Kansas City, KS; Department of Anatomy and Pharmacology, Three Gorges University College of Medicine, Yichang, China; Department of Urology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, China. Electronic address: bli@kumc.edu.
Benyi
B
Li
D000728:Androgens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
C410798:AR protein, human; D000728:Androgens; C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D011944:Receptors, Androgen; D002118:Calcium
Androgen receptor; CACNA1D; Calcium channel; Prostate cancer