TRPM8 and prostate cancer: to overexpress or repress, that is the question—comment on “Effects of TRPM8 on proliferation and motility of prostate cancer PC-3 cells” by Yang ZH et al. in Asian Journal of Andrology

Abstract

The changes of blood perfusion of contralateral testis after unilateral testicular torsion remain controversial. In this study, 28 New Zealand white male rabbits were randomly divided into five groups. Group A (n = 8), the control group, underwent a sham operation on the unilateral testis without inducing testicular torsion. In groups B, C, and D (n = 5 each), unilateral testicular torsion was induced, and, after 3, 6 or 24 h, respectively, detorsion was performed. In group E (n = 5), permanent unilateral testicular torsion was applied. Contrast-enhanced ultrasound was used to observe the blood perfusion of the contralateral testis at the following stages: pre-torsion (preopration), immediately post-torsion (postopration), pre-detorsion, immediately post-detorsion, and late-stage post-detorsion (6-12 h post-detorsion in groups B-D) or at a similar time point (15-21 h post-torsion in group E). Time-intensity curves were generated, and the following parameters were derived and analyzed: arrival time, time to peak intensity, peak intensity, and half-time of the descending peak intensity. The analysis revealed that blood perfusion of the contralateral testis increased immediately after testicular torsion on the opposite side (P < 0.05), which increased with prolonged testicular torsion of the other testis. This research demonstrated that contrast-enhanced ultrasound was valuable in evaluating blood perfusion of the contralateral testis after unilateral testicular torsion.

Anti-tumor activity of the TRPM8 inhibitor BCTC in prostate cancer DU145 cells

“…TRPM8 is a receptor-activated non-selective cation channel that is highly expressed in PCa cells, and in previous years has emerged as a promising prognostic marker and putative therapeutic target in PCa ( 11 , 16 , 17 , 22 ). Notably, TRPM8 induces tumor suppression when it is inhibited and also when activated.…”

“…Notably, TRPM8 induces tumor suppression when it is inhibited and also when activated. Since TRPM8 plays a key role in Ca 2+ homeostasis of prostate epithelial cells, either over-expression or repression of TRPM8 will lead to a loss of Ca 2+ homeostasis, and also to the degradation of cell viability ( 16 , 22 , 23 ). Previous studies have provided clear evidence that over-expression of TRPM8 in the androgen-independent PC3 cell line derived from metastatic sites in bone or the activation of TRPM8 using the classical TRPM8 agonist menthol in DU145 cells suppressed PCa cell viability ( 24 , 25 ).…”

Expression of TRPM8 in the prostate of rams and wethers

“…Reduced mRNA expression could be a result of downregulation of TRPM8 in wethers who do not have high/sufficient serum concentrations of testosterone, an activator of these channels. In the prostate TRPM8 is localized in the epithelial cells, and could be an important factor in calcium homeostasis of the cells ( Kulkarni, 2009 ). A majority of TRPM8 research in the prostate has focused on cancer research.…”

“…In prostate cancer cells, TRPM8 expression could only be detected in cells that were positive for the androgen receptor, and were not found on cells that did not produce the androgen receptor ( Bai et al, 2010 ). In healthy prostate epithelial cells, the expression of TRPM8 is rather low compared with carcinoma cells of the prostate where TRPM8 expression is increased and highly dependent on androgen concentrations ( Kulkarni, 2009 ). These channels are also known to be important for bladder function and to a larger extent male fertility ( Liu et al, 2016 ).…”

Ion channels as therapeutic antibody targets

“…252 As such, TRPM8 has been identified as a novel target for androgen-regulated prostate cancer, 253 where overexpression is androgen-dependent and required for tumor cell survival. Although the precise mechanism involved is unknown, 254 the influx of Ca 2+ and Na + in prostate cancer cells has been shown as necessary for survival and function, 255 and it is well established that Ca 2+ signaling regulates proliferation and apoptosis in cancer cells. In androgen-sensitive cell lines, such as LNCaP, testosterone activation of TRPM8 elevates basal Ca 2+ levels 252 whilst TRPM8 inhibition with a small molecule antagonist or siRNA results in cell death.…”