Menthol Induces Cell Death via the TRPM8 Channel in the Human Bladder Cancer Cell Line T24

Li, Qin; Wang, Xinghuan; Yang, Zhonghua; Wang, Bin; Li, Shilin

doi:10.1159/000264627

Cited by 90 publications

(54 citation statements)

References 72 publications

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“…TRPM8 knockdown using siRNA promoted cell proliferation and inhibited adhesion and invasiveness in Lewis lung cancer (LLC-2) cells [12]. Although TRPM8 expression and location were conformed previously in bladder cancer T24 cells [21], the expression levels of TRPM8 in UCB tissues and the relationship between TRPM8 expression and UCB clinicopathological characteristics remain to be poorly elucidated in the previous research.…”

Section: Discussionmentioning

confidence: 85%

Over-expression of TRPM8 is associated with poor prognosis in urothelial carcinoma of bladder

Xiao

Jiang

et al. 2014

Tumor Biol.

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Transient receptor protein (TRP) channels are frequently associated with tumors and are correlated to patient's outcome. We firstly investigated TRP channel melastatin 8 (TRPM8) expression in urothelial carcinoma of bladder (UCB) and its correlation with UCB clinicopathological features and additionally evaluated the association between TRPM8 expression and patients' survival rate to elucidate its role in bladder oncogenesis. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to examine TRPM8 messenger RNA (mRNA) expression in 36 pairs of freshly frozen UCB tissues and matched noncancerous tissues. Immunohistochemistry (IHC) was performed in 156 archived paraffin-embedded UCB samples to explore the correlation between TRPM8 protein and clinicopathological features. The association between TRPM8 expression and patient's survival rate was evaluated using the Kaplan-Meier method and multivariate Cox regression analysis, respectively. The expression levels of TRPM8 mRNA in UCB tissues were significantly higher than those in matched noncancerous tissues (P=0.016). Expression of TRPM8 protein in UCB was significantly and positively associated with histological grade (P=0.039) and tumor stage (P=0.037). Significant correlation between high TRPM8 expression and poor cumulative survival of UCB patients was shown using the Kaplan-Meier survival curve (P=0.039). TRPM8 was represented as an independent prognostic biomarker for UCB patients by multivariate Cox regression analysis (P=0.047). The present study provide the convincing evidence for the first time that over-expression of TRPM8 may play a role in the pathogenesis and progression of UCB, and TRPM8 may serve as an independent prognostic biomarker for UCB patients.

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Section: Discussionmentioning

confidence: 85%

Over-expression of TRPM8 is associated with poor prognosis in urothelial carcinoma of bladder

Xiao

Jiang

et al. 2014

Tumor Biol.

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“…TRPM8 also plays a role in prostate cancer (25) and human skin melanomas (26). In prostate cancer TRPM8 is now a tumour marker, and has a significant therapeutic potential in diagnosis and therapy of bladder cancer (27). Therefore, identification for potent and selective TRPM8 ligands is of direct clinical relevance.…”

Section: Introductionmentioning

confidence: 99%

Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship

et al. 2010

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-Purpose. Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivatives was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. Methods. Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. Results. The newly characterized ligands possess an up to six-fold higher potency (EC 50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC 50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. Conclusion. The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. ________________________________________________________________________________

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“…In conclusion, the above-mentioned mechanisms of TRPM8 regulation may be important for modulating normal and pathologic cold sensitivity as well as regulation of such processes, as cancer cells migration (40 -42) and viability (43), regulation of vascular tone (14), respiration (13), thermotaxis or chemotaxis (11), and bladder function (44).…”

Section: Discussionmentioning

confidence: 99%

Complex Regulation of the TRPM8 Cold Receptor Channel

Bavencoffe

Kondratskyi

Gkika

et al. 2011

Journal of Biological Chemistry

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Cold/menthol-activated TRPM8 (transient receptor potential channel melastatin member 8) is primarily expressed in sensory neurons, where it constitutes the principal receptor of environmental innocuous cold. TRPM8 has been shown to be regulated by multiple influences such as phosphorylation, pH, Ca 2؉ , and lipid messengers. One such messenger is arachidonic acid (AA), which has been shown to inhibit TRPM8 channel activity. However, the physiological pathways mediating the inhibitory effect of AA on TRPM8 still remain unknown. Here, we demonstrate that TRPM8 is regulated via M3 muscarinic acetylcholine receptor-coupled signaling cascade based on the activation of cytosolic phospholipase A2 (cPLA2) and cPLA2-catalyzed derivation of AA. Stimulation of M3 receptors heterologously co-expressed with TRPM8 in HEK-293 cells by nonselective muscarinic agonist, oxotremorine methiodide (Oxo-M), caused inhibition of TRPM8-mediated membrane current, which could be mimicked by AA and antagonized by pharmacological or siRNA-mediated cPLA2 silencing. Our results demonstrate the intracellular functional link between M3 receptor and TRPM8 channel via cPLA2/AA and suggest a novel physiological mechanism of arachidonate-mediated regulation of TRPM8 channel activity through muscarinic receptors. We also summarize the existing TRPM8 regulations and discuss their physiological and pathological significance.The members of the transient receptor potential (TRP) 5 superfamily of cationic channels display extraordinary diverse activation mechanisms and participate in the plethora of physiological and pathological processes (1), which made them the focus of intense research over the last decades. A number of TRPs, dubbed thermo-TRPs, from TRPV (vanilloid), TRPM (melastatin), and TRPA (ankyrin) subfamilies can be activated by various ambient temperatures ranging from noxious cold to noxious heat. They also respond to the chemical imitators of temperatures of various modalities and to the number of chemical and environmental irritants (2). Among them, TRPM8, which is activated by innocuous cold (Ͻ25°C) (3) and a well known cooling agent, peppermint oil component, menthol, represents a cold receptor. Except for the innocuous cold and menthol, TRPM8 can also be activated by some other cooling agents such as icilin and eucalyptol as well as by noncooling compounds hydroxy-citronellal, geraniol, and linalool (4). It has been shown that the mechanism of TRPM8 activation by cold and menthol involves negative shift in the voltage-dependent opening of the channel from very positive unphysiological membrane potentials toward physiological values (5, 6).Despite being proven as the principal detector of environmental cold (7-9), TRPM8 expression is by far not limited to the subset of cold-sensitive dorsal root ganglion and trigeminal sensory neurons in which it functions as cold-activated receptor channel. In fact, sizable TRPM8 expression was found in prostate (10), sperm (11), some epithelial (12, 13), and smooth muscle (14) cells as well as in canc...

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Menthol Induces Cell Death via the TRPM8 Channel in the Human Bladder Cancer Cell Line T24

Cited by 90 publications

References 72 publications

Over-expression of TRPM8 is associated with poor prognosis in urothelial carcinoma of bladder

Over-expression of TRPM8 is associated with poor prognosis in urothelial carcinoma of bladder

Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship

Complex Regulation of the TRPM8 Cold Receptor Channel

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