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1 Office of Chemical Safety (MDP 88), Therapeutic Goods Administration, Department of Health and Ageing, PO Box 100, Woden ACT 2606, Australia
2 Department of Medical Biochemistry, School of Medicine, Faculty of Health Sciences, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia
(Requests for offprints should be addressed to G Barritt; Email: greg.barritt{at}flinders.edu.au)
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Abstract |
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 Top Abstract IntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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Although there is evidence that TRPM8 is involved in thermo and pain sensation in sensory neurons, the knowledge of the functions of TRPM8 in other cell types, including prostate cancer cells, is very limited. The detection of TRPM8 in a number of normal urogenital tissues and the profile of up-regulated expression of TRPM8 in prostate cancer and other cancer cells suggest that this Ca2+-permeable channel may play diverse roles in different tissues.
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Structure of TRPM8 |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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). The S1–S4 transmembrane domains exhibit weak voltage-sensing properties. It is proposed that the pore of the channel is composed of the region between the S5 and S6 membrane-spanning sequences in a tetramer comprising, most likely, four TRPM8 polypeptides (McKemy et al. 2002). The amino terminus contains several TRPM homology sequences, while the large carboxy terminus contains the TRP box (a sequence common to each member of the TRPV, TRPC and TRPM families) and eight potential N-linked glycosylation sites. Unlike many other members of the TRP family, no ankyrin repeat elements are present in the amino terminus (Tsavaler et al. 2001, Peier et al. 2002, Clapham 2003). Electrophysiological studies conducted with TRPM8 heterologously expressed in mammalian cells indicate that the protein mediates an outwardly rectifying current with a selectivity for Ca2+: Na+ of 3 : 1 (McKemy et al. 2002, Peier et al. 2002).
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Activation signals and mechanisms for TRPM8 |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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) (McKemy et al. 2002, Peier et al. 2002, Behrendt et al. 2004, Brauchi et al. 2004, Voets et al. 2004). Capsazepine (shown in Fig. 2b) is an antagonist of menthol activation of TRPM8 (Behrendt et al. 2004). Other antagonists include N-(4-tert.butylphenyl)-4-(3-chloropyridin-2-yl)tetra-hydropyrazine-1(2H) carboxamite (BCTC) (Fig. 2b) and thiol BCTC (Behrendt et al. 2004). The activation of TRPM8 by cold and icilin, but not by menthol, is modulated by intracellular pH (Andersson et al. 2004).
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Another agent that plays an important role in the activation of TRPM8 is phosphatidylinositol 4,5-bisphosphate (PIP2). Liu & Qin (2005) showed that the inactivation (desensitisation) of the TRPM8 channel is prevented by inhibitors of phospholipid phosphatases. Moreover, the application of exogenous PIP2 was found to both activate the channel directly and to restore activity after desensitisation (Liu & Qin 2005). Using a slightly different experimental strategy, Rohacs et al. (2005) provided evidence that PIP2 is necessary for the activation of TRPM8 by cold or cooling agents. Moreover, PIP2 itself (in the absence of cold or a cooling agent) could also activate the channel. Cold or a cooling agent increases the apparent affinity of TRPM8 for PIP2 and it is proposed that cooling activates the channel by increasing the sensitivity to PIP2. Evidence has been obtained to indicate that PIP2 binds to positive changes in the TRP motif in the cytoplasmic carboxy terminus (shown schematically in Fig. 1
). As pointed out by Rohacs et al. (2005), the activation mechanisms of TRPM8 are undoubtedly complex. It is likely that the role of PIP2 is part of, or linked to, the effects of cold and cooling agents in changing the activation energy of the channel (Voets et al. 2004). Confirmation of these ideas will require further experiments.
Ca2+ plays an important role in regulating the activity of TRPM8. Recent studies by Chuang et al. (2004) have shown that the activation of TRPM8 by icilin requires an increase in the cytoplasmic Ca2+ concentration ([Ca2+]cyt) at the cytoplasmic mouth of the channel i.e. the flow of Ca2+ through the channel (Fig. 1). They suggested that this requirement for Ca2+ might represent the coincidence detection of signals by TRPM8 (Chuang et al. 2004). These authors also provided evidence that indicates that the region of the TRPM8 polypeptide that appears to interact with icilin is similar in structure to the region of hot-sensing TRPV1 that interacts with capsaicin.
Ca2+ inflow also plays a role in modulating (desensitising) TRPM8. Thus it has been found that Ca2+ inflow through TRPM8 activates phospholipase C (PLC) (possibly PLC
1) which hydrolyses PIP2, leading to a decrease in PIP2 and inhibition (desensitisation) of channel activity (Fig. 1) (Rohacs et al. 2005). This may be one of numerous examples (for many types of Ca2+ permeable channel) of the physiological importance of limiting the amount of Ca2+ which enters the cell via the open channel, and hence the necessity of there being effective mechanisms for achieving this.
Several research groups have compared the properties of the cold-sensing TRPM8 channels with those of the hot-sensing TRPV channels. It was found that TRPM8 is inhibited by 2-aminoethoxydiphenyl borate (2-APB) (Hu et al. 2004). 2-APB inhibits several types of plasma membrane Ca2+-permeable channels and, under some conditions, it also inhibits inositol 1,4,5-trisphosphate receptors (Bootman et al. 2002). 2-APB can be used to distinguish TRPM8 from TRPV1, V2 and V3, since it activates TRPV1, V2 and V3 but inhibits TRPM8 (Hu et al. 2004). These observations most likely reflect differences in either the pores of the channels or in the activation mechanisms.
Other similarities and differences between TRPM8 and TRPV1 have been described by Weil et al. (2005) using the whole cell patch-clamp technique to study channel function. They showed that TRPM8 activity is modified by ethanol, TRPM8 is not affected by extracellular H+ whereas TRPV1 does respond to extracellular H+, and many of the TRPV1 antagonists, including capsazepine, BCTC, (2R)-4-(3-chloro-2 pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1 piperazonecarboxamide (CTPC) and SB-452533, are also antagonists of TRPM8. These results have implications for both the structure and mechanism of activation of TRPM8, and also highlight potential difficulties in developing pharmaceutical interventions selective for TRPM8.
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Expression and functions of TRPM8 in neuronal cells |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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. Further evidence for the function of TRPM8 as a sensor for cold in sensory neuronal cells has come from the transient transfection of cultured hippocampal neurones with TRPM8. This conferred sensitivity to cold and menthol that is not exhibited by non-transfected hippocampal neurones (de la Pena et al. 2005).
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Expression of TRPM8 in prostate cancer cells |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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). Henshall et al. (2003) observed that with anti-androgen therapy, the expression of TRPM8 was greatly reduced. They also showed that TRPM8 expression is decreased when prostate cancer cells become androgen-independent, suggesting that TRPM8 is regulated by androgens (Henshall et al. 2003). The degree of expression of TRPM8 in prostate cancer tissue appears to be quite variable (Tsavaler et al. 2001, Henshall et al. 2003, Kiessling et al. 2003). Kiessling et al. (2003) examined prostate cancer tissue from 33 prostate cancer patients and found high but variable levels of TRPM8 mRNA expression in both tumorigenic and normal prostate tissue. However, a statistically significant greater expression of TRPM8 was observed in tumorigenic compared with normal tissue. No clear correlation of TRPM8 expression with the severity of prostate cancer was, however, observed.
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In malignant tissue specimens from patients with a total serum PSA concentration in the ‘grey-zone’ of 4–10 ng/ml, TRPM8 mRNA, but not PSA mRNA was significantly elevated. Thus the detection of TRPM8 expression could be useful in the differential diagnosis of prostate cancer in biopsy specimens to facilitate therapeutic decisions particularly in ambiguous cases often found in this total PSA ‘grey-zone’. More interestingly, in identified groups of low- and high-grade prostate cancer, significant differences in expression between malignant and non-malignant tissue samples were found for TRPM8 but not for other prostate cancer markers, including PSA. It was concluded that, compared with the other markers (PSA, hK2 and PSCA), TRPM8 is a more specific indicator of prostate cancer and a potential candidate for targetted gene therapy or other interventions (Fuessel et al. 2003). However, as discussed below, expression of TRPM8 in prostate cancer cells is closely linked to the presence of a functional androgen receptor. Bidaux et al. (2005) have drawn attention to the complexities caused by this link and hence in using TRPM8 as a prognostic marker for prostate cancer.
A significant proportion of TRPM8 is observed in the plasma membrane of prostate cancer cells, although the protein has also been observed in intracellular membranes (Zhang & Barritt 2004). Extracellular domains of the protein can potentially activate cytotoxic T-lymphocytes. One such region, the GLMKYIGEV, has been identified (Kiessling et al. 2003). This may provide an endogenous mechanism that enhances the destruction of prostate cancer cells expressing TRPM8 — part of the normal immunological defence mechanisms. Loss of TRPM8 expression in metastatic prostate cancer cells may, therefore, be associated with a reduction in prostate cancer cell destruction. On the other hand, the activation of cytotoxic T-lymphocytes by the GLMKYIGEV region may offer the possibility of an immunotherapeutic approach to killing prostate cancer cells based on this or another TRPM8 peptide as target (Kiessling et al. 2003).
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Regulation of TRPM8 by androgens in prostate cancer cells |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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The question of what mechanism underlies the androgen regulation of TRPM8 in androgen-responsive prostate cancer cells has been addressed, and several putative androgen response elements have been detected (Zhang & Barritt 2004, Bidaux et al. 2005). Analysis of 5' flank regions of the TRPM8 gene using GenoMatix reveals that a region which spans 1500 bp upstream of the transcription initiation code in the TRPM8 gene may be the core promoter for TRPM8 DNA transcription. This promoter region contains a variety of putative transcriptional factor binding sites including at least three TATA boxes, a transcription factor Sp1, a transcript enhancer factor Tef, three NKX3.1 binding sites and an androgen-responsive element (Table 2, Fig. 4). The last mentioned exhibits a high degree of homology to a motif corresponding to the TRANSFAC androgen-responsive element consensus sequence (c.f. Zhang & Barritt 2004, Bidaux et al. 2005). Further analysis reveals another nine putative androgen-responsive elements in the introns of the TRPM8 gene (Fig. 4), and two in the 3' untranslated region. It is possible that in androgen-responsive prostate cancer cells (which have functional androgen receptors) the androgen–androgen receptor complex binds with androgen response elements in either the promoter region or introns in the TRPM8 gene. Together with other transcription co-factors, this may initiate TRPM8 gene transcription.
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Physiological functions of TRPM8 in prostate cancer cells |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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It has been proposed that, in LNCaP cells, an increased growth rate correlates with an increase in the amount of Ca2+ in intracellular stores, whereas a decreased rate of growth correlates with a reduced load of Ca2+ in intracellular stores (Legrand et al. 2001). TRPM8 may, with other ER-located Ca2+ pool regulators (e.g. ER (Ca2++Mg2+)ATPase), modulate the amount of Ca2+ in intracellular stores and subsequently regulate cell growth and proliferation (Fig. 5A).
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). It has been suggested that TRPM8 serves as a cold sensor in the prostate (Stein et al. 2004). Such a function has also recently been suggested for TRPM8 in the bladder (Tsukimi et al. 2005). TRPM8 may also be involved in other functions such as the regulation of proliferation and/or apoptosis (and hence the control of cell number) and in ion and protein secretion in prostate epithelial cells (Zhang & Barritt 2004). One interesting possibility comes from the recent observation that geraniol activates TRPM8 (Behrendt et al. 2004). The pyrophosphate ester of geraniol is an intermediate in cholesterol synthesis (Voet & Voet 1990), and geraniol enhances cell proliferation in prostate epithelium (Paubert-Braquet et al. 1998). Thus it is possible that, in prostate epithelial cells, TRPM8 is involved in the regulation of cell proliferation and responds to geraniol as an intracellular messenger (Zhang & Barritt 2004). A more detailed study of the tissue and intracellular locations of the TRPM8 protein in the prostate has shown that TRPM8 is principally expressed in prostate epithelial cells (Bidaux et al. 2005). A low level of TRPM8 expression was also found in smooth muscle cells. In prostate epithelial cells, the highest level of TRPM8 expression was seen in the apical region of secretory epithelial cells, with much lower amounts of TRPM8 found in the basal regions. Expression of TRPM8 in secretory epithelial cells of the prostate decreased with time as the cells were grown in primary culture and became dedifferentiated. Bidaux et al. (2005) have suggested that TRPM8 is involved in the secretory function of prostate epithelial cells. Secretory products include citric acid, fibrinolysin, acid phosphatase, several other enzymes and lipids. Noting the androgen-dependence of TRPM8 expression and a role for androgens in oocyte fertilisation, these authors have suggested that one of the functions of androgen-regulated TRPM8 is in fertilisation.
In addition to normal prostate epithelium, TRPM8 is also detected in a number of urogenital tissues including testis, seminiferous tubules, scrotal skin, and bladder urothelium (Tsukimi et al. 2005) (Table 1). This systemic expression profile implies that TRPM8 may have yet to be identified roles associated with reproduction and/or sexuality.
On the basis of the observation that TRPM8 expression is upregulated in organ-confined prostate cancer cells and in a number of other cancerous cell types, TRPM8 could function as an oncogene. TRPM8 may contribute to the initiation, promotion and progression of carcinogenesis by disturbing Ca2+ homeostasis in preAneoplastic cells. It has been reported that early pre-neoplastic cells are highly susceptible to apoptosis, whereas later pre-neoplastic cells are quite resistant (Preston et al. 1997). Moreover, increases in [Ca2+]cyt and intra-organelle Ca2+ play key roles in apoptosis (Mattson & Chan 2003). Although several hypotheses have been proposed to explain the resistance of cells (such as androgen-unresponsive prostate cancer cells) to apoptosis, a plausible mechanism involving Ca2+ signalling has been presented (reviewed in Prevarskaya et al. 2004) in which reduced Ca2+ levels in the ER were observed in early pre-neoplastic cells that undergo apoptosis compared with a higher level of stored Ca2+ in the ER in late pre-neoplastic cells. Over-expressed or upregulated TRPM8 channels could cause an increase in [Ca2+]cyt and an overfilling of ER Ca2+ store and this change in Ca2+ homeostasis would make the late pre-neoplastic cells more resistant to apoptotic stimuli and subsequently promote cell transformation into a neoplastic stage.
In addition, the detection of putative binding sites for tumour suppressor protein p53, prostate-specific homeodomain protein NKX3.1, and zinc-finger binding protein-89 (ZBP-89; Merchant et al. 2003) (Table 2) in the TRPM8 gene promoter region implies that TRPM8 may serve as a downstream target of tumour-suppressor genes. (ZBP-89 is a butyrate-regulated co-activator of p53, and is able to induce p21(Waf1) gene expression through both p53-dependent and -independent mechanisms to inhibit cell growth (Merchant et al. 2003).) Thus TRPM8 may be involved in the regulation of cell growth and carcinogenesis. Taken together, the above results suggest that TRPM8 is a novel prostate cancer bio-marker, is likely to play an important role in the pathophysiology of prostate epithelial cells, and is a potential target for the action of drugs in the treatment of prostate cancer.
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The consequences of sustained activation of TRPM8 induced by pharmacological intervention in prostate cancer cells |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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). These effects most likely reflect a pathophysiological action of TRPM8, as it is unlikely that TRPM8 would normally be activated in a sustained manner. Interestingly, these findings may provide an explanation for the chemopreventive role of menthol on rat mammary tumours initiated by 7,12-dimethylbenz[a]anthracene (Russin et al. 1989) because TRPM8 is also expressed at significant levels in breast cancer cells (Table 1). Further experiments are needed to test the hypothesis and to evaluate whether menthol and its analogues could be promising agents for the chemoprevention of prostate and other cancers. |
Conclusions |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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TRPM8 is potentially a valuable diagnostic tissue marker and prognostic indicator for the progress of prostate cancer. Additional knowledge, which might establish this role for TRPM8 could include measurement of TRPM8 expression at the protein (as well as the mRNA) level. Further studies are needed to compare TRPM8 expression with other established prostate cancer markers in terms of accuracy and probability. The limitation of using TRPM8 as a marker is that prostate tissues are needed for the examination of TRPM8 levels. The regulation of TRPM8 expression by androgens is important in terms of both fundamental knowledge and understanding the role of TRPM8 in prostate cancer. Further experiments might be directed at identifying androgen response elements and perhaps other hormone response elements in the promoter and intron regions, and at understanding the mechanisms underlying up-regulation of TRPM8 in cancerous tissues. Finally, TRPM8 may be a potential target for pharmaceutical or genetic interventions for the treatment of prostate cancer and other cancers with over-expression of TRPM8. Further experiments might include screening for the specific and potent agonists for activation of the TRPM8 channel and exploring the strategy in vivo.
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Acknowledgements |
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which was originally published in Cancer Research. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work. |
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TopAbstractIntroductionStructure of TRPM8Activation signals and...Expression and functions of...Expression of TRPM8 in...Regulation of TRPM8 by...Physiological functions of TRPM8...The consequences of sustained...ConclusionsReferences |
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 A. Malkia, R. Madrid, V. Meseguer, E. de la Pena, M. Valero, C. Belmonte, and F. Viana Bidirectional shifts of TRPM8 channel gating by temperature and chemical agents modulate the cold sensitivity of mammalian thermoreceptors J. Physiol., May 15, 2007; 581(1): 155 - 174. [Abstract] [Full Text] [PDF]
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K. Kiselyov, A. Soyombo, and S. Muallem TRPpathies J. Physiol., February 1, 2007; 578(3): 641 - 653. [Abstract] [Full Text] [PDF]
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 B. Nilius, G. Owsianik, T. Voets, and J. A. Peters Transient Receptor Potential Cation Channels in Disease Physiol Rev, January 1, 2007; 87(1): 165 - 217. [Abstract] [Full Text] [PDF]
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 T. Gudermann and S. Roelle Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides Endocr. Relat. Cancer, December 1, 2006; 13(4): 1069 - 1084. [Abstract] [Full Text] [PDF]
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