Abstract
In prostate carcinogenesis, androgens are known to control the expression of the transient receptor potential melastatin 8 (TRPM8) protein via activation of androgen receptor (AR). Overexpression and/or activity of TRPM8 channel was shown to suppress prostate cancer (PCa) cell migration. Here we report that at certain concentrations androgens facilitate PCa cell migration. We show that underlying mechanism is inhibition of TRPM8 by activated AR which interacts with the channel within lipid rafts microdomains of the plasma membrane. Thus, our study has identified an additional nongenomic mechanism of the TRPM8 channel regulation by androgens that should be taken into account upon the development of novel therapeutic strategies.
Highlights
In developed countries, prostate cancer (PCa) is the second most frequently diagnosed cancer and the third most common cause of death by cancer in men[1]
In either case, application of the 1 μM of the selective transient receptor potential melastatin 8 (TRPM8) antagonist, M8-B16, completely abolished both, the initial [Ca2+]c transient (Fig. 1b, d; Fig. S1B, D) and the sustained response (Fig. 1c, e; Fig. S1C, E). This strongly suggests that both phases of the [Ca2+]c response to either icilin or menthol intimately depend on TRPM8 channel activity
In the present study, we report that androgens directly regulate TRPM8-mediated PCa cell migration
Summary
Prostate cancer (PCa) is the second most frequently diagnosed cancer and the third most common cause of death by cancer in men[1]. PCa development starts from epithelial cells in the peripheral zone of the prostate and is androgen controlled[2]. Metastasis development at late PCa stages is the main cause of mortality. Survival and proliferation of some PCa cells often become androgen-independent, allowing to escape the above treatment and giving rise to more aggressive forms of cancer[3]. This androgen insensitivity significantly increases PCa mortality rate and suggests that control of PCa progression by androgens have multiple modalities
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