Abstract
Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers.
Highlights
Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, its mechanism of action remains unclear
Regulation of TRPM8 by the androgen/androgen receptor (AR) axis remains debated, pharmacologic modulation of the channel is frequently proposed in prostate cancer (PC) t herapy[20,22,23,24]
Three new analogs (4, 5, and 9) were synthesized and characterized by patch clamp electrophysiological assays. These chemotypes are attractive due to the potent and selective cytotoxicity shown in a previous drug discovery screening[34]
Summary
Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, its mechanism of action remains unclear. The transient receptor potential melastatin-8 (TRPM8), a widely distributed non-selective calcium permeable ion channel, was initially characterized as a cold sensing c hannel[1,2]. It is involved in a plethora of pathological processes, such as p ain3,4, migraine[5], overactive as well as painful bladder s yndromes[6,7] and dry eye syndrome or excessive lacrimation d ysfunction[8]. TRPM8 channel is directly involved in calcium h omeostasis[9] and can be regulated by a ndrogens10, estrogens11, neurotrophins[12] and growth factors[13] As such, it represents a very promising target in solid cancers[13,14], including prostate cancer (PC)[9,15]. Regulation of TRPM8 by the androgen/AR axis remains debated, pharmacologic modulation of the channel is frequently proposed in PC t herapy[20,22,23,24]
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