Roberta Aimar, Giulia Ottaviano
PROSTATE CANCER
Introduction:
Ion channels have been shown to be implicated in several aspects of cancer development in various organs including the prostate. These include sodium channels in cell invasion and migration, voltage-dependent calcium (Ca++) channels in neuroendocrine differentiation, non voltage-dependent TRP and ORAI Ca++ channels in migration , or potassium (K+) channels in cell proliferation.
Calcium signaling is a common mechanism involved in the majority of cellular functions, and Ca++ homeostasisis tightly modulated by multiple channel mechanisms in all excitable and many nonexcitable cells. Functional machineries for calcium influx and intracellular calcium release exist in prostate cancer cells, and maintenance of intracellular Ca++ pool is required for cell growth, whereas blocking Ca++ influx reduces cell growth and invasion as well as prostate-specific antigen (PSA) secretion. There are several lines of evidence that Ca++ influx is involved in cell growth,invasion,and death of prostate cancer cells.
(Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.2013)
Inverse Association between Prostate Cancer and the Use of Calcium Channel Blockers.
Because calcium channel blockers (CCB) alter calcium signals and thereby interfere with cellular apoptosis, the relationship between the use of these drugs and cancer of the prostate and other organs is of interest. The rationale for an association between calcium channel blocker use and cancer is based on the hypothesis that calcium channel blockers block calcium signal mediated apoptosis and thereby increase the risk of cancer. A study published on February 2004 by Jose D. Debes et al. investigated the association between daily use of calcium channel blockers and prostate cancer in a community-based cohort of men who participated in a longitudinal study of lower urinary tract symptoms. Study subjects were men ages 40 to 79 years. At baseline, participants underwent an interview to determine all medications taken on a daily basis, including calcium channel blockers and to elicit a family history of prostate cancer. During follow-up, all men with a histological diagnosis of prostate cancer were identified through patient self-report and by a review of the complete medical record. Over 12,668 person years of follow-up, 15 (6.8%) of 220 calcium channel blocker users and 120 (10.5%) of 1142 nonusers developed prostate cancer (P 0.09; odds ratio, 0.62; 95% confidence interval, 0.36 –1.10). With adjustment for age and family history of prostate cancer, the risk (odds ratio, 95% confidence interval) of prostate cancer was 0.55 (0.31– 0.97) in calcium channel blocker users compared with nonusers. In analyses stratified by family history of prostate cancer, the risk of prostate cancer was 0.45 (0.23– 0.88) in men without a family history and 2.64 (0.82– 8.47) in men with a family history of prostate cancer (P 0.006). These findings suggest an inverse association between prostate cancer and daily use of calcium channel blockers that varies by family history of prostate cancer.
(Inverse association between prostate cancer and the use of calcium channel blockers.2004)
Ten years later, Michael A. Poch et al. published a study on the same topic. Medication use, PCa aggressiveness and post-RP outcome were retrieved from a prospectively populated database that contains clinical and outcome for RP patients at Roswell Park Cancer Institute (RPCI) from 1993 to 2010. The database was queried for antihypertensive medication use at diagnosis for patients with 1 year follow-up. Recurrence was defined using NCCN guidelines. Chi-Square tests assessed the relationship between CCB use and PCa aggressiveness. Cox regression models compared the distribution of progression- free survival (PFS) and overall survival (OS) with adjustment for covariates. Results for association between CCB usage and PCa aggressiveness were validated using data from the population-based North Carolina-Louisiana Prostate Cancer Project (PCaP). Results are: 48%, 37%, and 15% of RPCI’s RP patients (n ¼ 875) had low, intermediate, and high aggressive PCa, respectively. 104 (11%) had a history of CCB use. Patients taking CCBs were more likely to be older, have a higher BMI and use additional anti-hypertensive medications. Diagnostic PSA levels, PCa aggressiveness, and margin status were similar for CCB users and non-users. PFS and OS did not differ between the two groups. Tumor aggressiveness was associated with PFS. CCB use in the PCaP study population was not associated with PCa aggressiveness. In conclusion CCB use is not associated with PCa aggressiveness at diagnosis, PFS or OS.
(The association between calcium channel blocker use and prostate cancer outcome.2013)
And then .. what 'is the truth?
A study of Ruibao Chen 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, they found that L-type calcium channel CACNA1D gene expression levels in cancer tissues were significantly higher than non-cancer tissues in 14 of 15 published complementary deoxyribonucleic acid microarray datasets,of which 9 datasets 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 Ca2þ influx, AR transactivation, and cell grow thin 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 Ca2þ influx, AR activation, and cell growth in prostate cancer cells.
(Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.2013)
Conclusion
Probably not all of the calcium channels are involved in the pathogenesis of prostate cancer, but only some specific types; Therefore, blockers of calcium channels determine only partial protection from cancer cell grow.
Our thesis about specific types of Ca++ channel is supported by an article wrote by Lei Zhang et al
It has emerged that the transient receptor potential (TRP) family of Ca2+-and Na+-permeable channels plays a diverse and important role in cell biology and in pathology. One member of this family, TRPM8, is highly expressed in prostate cancer cells but the physiological and pathological functions of TRPM8 in these cells are not known.
In prostate epithelial cells, expression of TRPM8 is regulated by androgen and is elevated in androgen-sensitive cancerous cells compared with normal cells. While there is some evidence that in prostate cancer cells Ca2+ and Na+ inflow through TRPM8 is necessary for survival and function, including secretion at the apical membrane, the function of TRPM8 in these cells is not really known.
TRPM8 is a potential tissue marker in differential diagnosis and a potential prognostic marker for androgen-unresponsive and metastatic prostate cancer. As a consequence of its ability to convey Ca2+ and Na+ and its expression in only a limited number of cell types, TRPM8 is considered to be a promising target for pharmaceutical, immunological and genetic interventions for the treatment of prostate cancer.
(TRPM8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function?.2006)
