TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β‐catenin signalling

Pagano, Ester; Romano, Barbara; Cicia, Donatella; Iannotti, Fabio Arturo; Venneri, Tommaso; Lucariello, Giuseppe; Nanì, Maria Francesca; Cattaneo, Fabio; Cicco, Paola De; D’Armiento, Maria; Luca, Marcello De; Lionetti, Ruggiero; Lama, Stefania; Stiuso, Paola; Zoppoli, Pietro; Falco, Geppino; Marchianò, Silvia; Fiorucci, Stefano; Capasso, Raffaele; Marzo, Vincenzo Di; Borrelli, Francesca; Izzo, Angelo A.

doi:10.1111/bph.15960

Cited by 21 publications

(14 citation statements)

References 69 publications

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“…In macrophages, TRPM8 regulates MAPK signaling pathways such as MAPK/ERK and MAPK/P38 [ 10 ]. Another study showed that TRPM8 activation can inhibit the development of colorectal cancer by suppressing the Wnt/β-catenin signaling pathway [ 35 ]. Our study discovered for the first time that the activation of TRPM8 mainly inhibited the SP release from primary sensory neurons via Wnt/β-catenin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis

Zhang,

Yan,

Kang

et al. 2024

Cell Death Dis

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Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8’s role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients’ data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3β from the Wnt/β-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven β-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3β, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

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Section: Discussionmentioning

confidence: 99%

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis

Zhang,

Yan,

Kang

et al. 2024

Cell Death Dis

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“…Other agents may be important adjuncts to CRC therapy in conjunction with cannabinoids. For example, upregulation of the ion channel protein TRPM8 is associated with a poor outcome in CRC patients, and the TRPM8 ligand WS12 represses colon tumorigenesis in mice, at least in part through downregulation of canonical Wnt signaling [58]. Thus, synthetic organics like WS12 may synergize with cannabinoids in the treatment of CRC.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy and Cannabis: A Harmful Drug Interaction or Reefer Madness?

Piper,

Tian,

Saini

et al. 2024

Cancers

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A retrospective (N = 140) and a prospective (N = 102) observational Israeli study by Bar-Sela and colleagues about cannabis potentially adversely impacting the response to immunotherapy have together been cited 202 times, including by clinical practice guidelines. There have also been concerns on PubPeer outlining irregularities and unverifiable information in their statistics and numerous errors in calculating percentages. This reanalysis attempted to verify the data analysis while including non-parametric statistics. The corrected prospective report contained 22 p-values, but only one (4.5%) could be verified despite the authors being transparent about the N and statistics employed. Cannabis users were significantly (p < 0.0025) younger than non-users, but this was not reported in the retrospective report. There were also errors in percentage calculations (e.g., 13/34 reported as 22.0% instead of 38.2%). Overall, these observational investigations, and especially the prospective, appear to contain gross inaccuracies which could impact the statistical decisions (i.e., significant findings reported as non-significant or vice-versa). Although it is mechanistically plausible that cannabis could have immunosuppressive effects which inhibit the response to immunotherapy, these two reports should be viewed cautiously. Larger prospective studies of this purported drug interaction that account for potential confounds (e.g., greater nicotine smoking among cannabis users) may be warranted.

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“…Whole protein lysates were obtained as described elsewhere [44] by incubating the cells with ice-cold RIPA buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40, 1 mM EDTA, 0.25% sodium deoxycholate, 1 mM NaF, 10 µM Na 3 VO 4 , 1 mM phenylmethylsulfonylfluoride, 10 µg/mL aprotinin, 10 µg/mL pepstatin, 10 µg/mL leupeptin). Nuclear protein purification was performed with a Qproteome kit (Qiagen, Hiden, Germany) following the manufacturer's instructions.…”

Section: Protein Extraction and Western Blotmentioning

confidence: 99%

Formyl-Peptide Receptor 2 Signaling Modulates SLC7A11/xCT Expression and Activity in Tumor Cells

Pecchillo Cimmino,

Punziano,

Panico

et al. 2024

Antioxidants

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Cancer cells exhibit high levels of oxidative stress and consequently require a high amount of cysteine for glutathione synthesis. Solute Carrier Family 7 Member 11 (SLC7A11), or xCT, mediates the cellular uptake of cystine in exchange for intracellular glutamate; imported extracellular cystine is reduced to cysteine in the cytosol through a NADPH-consuming reduction reaction. SLC7A11/xCT expression is under the control of stress-inducing conditions and of several transcription factors, such as NRF2 and ATF4. Formyl-peptide receptor 2 (FPR2) belongs to the FPR family, which transduces chemotactic signals mediating either inflammatory or anti-inflammatory responses according to the nature of its ligands and/or FPR2 binding with other FPR isoforms. The repertoire of FPR2 agonists with anti-inflammatory activities comprises WKYMVm peptide and Annexin A1 (ANXA1), and the downstream effects of the intracellular signaling cascades triggered by FPR2 include NADPH oxidase (NOX)-dependent generation of reactive oxygen species. Herein, we demonstrate that stimulation of CaLu-6 cells with either WKYMVm or ANXA1: (i) induces the redox-regulated activation of SLC7A11/xCT; (ii) promotes the synthesis of glutathione; (iii) prevents lipid peroxidation; and (iv) favors NRF2 nuclear translocation and activation. In conclusion, our overall results demonstrate that FPR2 agonists and NOX modulate SLC7A11/xCT expression and activity, thereby identifying a novel regulative pathway of the cystine/glutamate antiport that represents a new potential therapeutical target for the treatment of human cancers.

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TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β‐catenin signalling

Abstract: Background and Purpose: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC).

Cited by 21 publications

References 69 publications

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis

Immunotherapy and Cannabis: A Harmful Drug Interaction or Reefer Madness?

Formyl-Peptide Receptor 2 Signaling Modulates SLC7A11/xCT Expression and Activity in Tumor Cells

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