The role of TRPA1 in lung cancer

Introduction

Lung cancer is the leading cause of cancer related death worldwide (1,2) and the second most common type of cancer. One of the earliest symptoms of lung cancer is a chronic cough which can occur in approximately 30–70% of patients prior to diagnosis (3,4). Moreover, it appears that traditionally there is a lack of research into cough symptoms within this population (5).

The cough reflex occurs following activation of ion channels present on vagal sensory afferent nerves by endogenous or exogenous stimuli (6). These ion channels include the transient receptor potential (TRP) channel family of cation-selective channels, which act as cell sensors and respond to external environmental changes. A significant body of research has linked TRP receptors as key channels associated with pain and pain management (7,8), but more recently links between these receptors and cancer development are beginning to emerge (9).

Originally isolated from human fibroblasts (10), transient receptor potential ankyrin-1 (TRPA1) is known to be activated by cigarette smoke (11) and suggested to be a key player in e-cigarette sensitivity (12,13). While there is some data within the pulmonary setting regarding the potential roles TRPA1 plays in the pro-inflammatory milieu (14,15) and on endoplasmic reticulum stress (16), currently there is a paucity of research regarding the role TRPA1 in non-small cell lung carcinoma (NSCLC) carcinogenesis.

The purpose of this review therefore is to examine the potential roles that TRPA1 plays in lung cancer. We discuss the current knowledge surrounding the biology of TRPA1, its functionality and dysregulation in the molecular setting, and explore the potential links between TRPA1 and lung cancer development. Finally, we describe the current development of therapies aimed at targeting TRPA1 with respect to pain management and discuss how targeting TRPA1 may have a role in lung cancer either as a direct target for therapy or in the management of pain in these patients.

Lung cancer

Lung cancer is primarily categorised as either small cell lung carcinoma (SCLC) or NSCLC. NSCLC is further separated into squamous cell carcinoma (SCC), lung adenocarcinoma (LUAD) and adenosquamous carcinoma.

SCLC accounts for 15% of all lung cancer diagnoses (17). It is heavily associated with cigarette smoking and has a poor 5-year overall survival (OS) of 5%. SCLC employs oncogenic calcium signalling, in addition to other mechanisms, to promote cell proliferation and survival (17). SCLC has a rapid proliferation rate and bears a neuroendocrine phenotype, typically demonstrating positivity for neuroendocrine immunohistochemical markers.

NSCLC accounts for 85% of lung cancer diagnoses (18). Five-year survival for NSCLC is low, at 15% for all stage disease. Approximately 70% of patients are at an advanced stage at diagnosis, often when metastasis have already developed (19), which limits surgical treatment options (20). This cohort of patients typically rely on targeted immunological or chemotherapeutic strategies for disease management. LUAD specifically has a poor 5-year survival of 20–30% (21,22), which decreases to 5% for stage IV disease (23). A key challenge with non-surgical treatment strategies is the fact that LUAD is subject to elevated levels of drug resistance over time (22). This significantly impacts treatment strategies and long-term patient survival. Therefore, the ability to provide a diagnosis at an earlier stage is critical to improve patient survival and provide curative treatment options for patients.

TRP channels

TRP channels are a superfamily of nonselective cation channels (19) which have key roles in ion signal transduction pathways (22). TRP channels all show sequence homology to the Drosophila TRP protein (19). A number of subfamilies have been identified (24), including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin), TRPML (mucolipin), and TRPN (Drosophila No mechanoreceptor potential C) (22,25,26), all of which have varying cation selectivity and various types of gating (ligand, mechanical, temperature, etc.) (19). TRP channels have key functions in a range of physiological activities, including bladder and airway hypersensitivity, cell growth and survival (22,27). The expression of TRP channels is also upregulated in inflammatory respiratory diseases (6). Of the various receptors in this superfamily, one of key interest in the respiratory system and of emerging importance in a variety of cancers is transient receptor potential ankyrin-1 (TRPA1).

TRPA1, part of the TRP superfamily and the only discovered member of the ankyrin family (26), is a nonselective ion channel involved in numerous physiological functions (28) which include thermoregulation, nociception, phagocytosis, cell motility and inflammatory pain sensation (19,29). The number of activators of TRPA1 far exceeds that of any other TRP channel (6), adding to its physiological importance. TRPA1 is involved in a variety of disease processes (30), particularly in the respiratory system, due to its unique activation mechanisms. It also plays a role in the development of neurogenic inflammation and acute lung injury (17). Similar to TRPV1, TRPA1 can be activated by the indirect endogenous mediators prostaglandin E2 and bradykinin (17,31). TRPA1 is expressed in both neuronal and non-neuronal cells, however there is currently limited information regarding the exact roles of TRPA1 in the non-neuronal cells of the respiratory system (17). This represents an important knowledge gap in scientific literature.

TRPA1 functionality and dysregulation

One of the key features of TRPA1 is its high permeability for calcium (32). Once TRPA1 is activated, calcium rapidly enters the cell causing depolarization and transduction of the sensory signal. TRPA1 can be activated by both endogenous and exogenous stimuli (25,33), both electrophilic and non-electrophilic (32). Known agonists include compounds such as acrolein, wood smoke, formalin, cigarette smoke, cinnamaldehyde and reactive oxygen species (ROS) (6,34).

Various cell types have been found to express TRPA1. These include lung fibroblasts, Schwann cells, epithelial cells, cardiac fibroblasts, pancreatic beta cells, enterochromaffin cells and T lymphocytes (25). Structurally, the human-derived TRPA1 protein contains approximately 1,100 amino acids with a relative molecular mass of 120–130 kilodaltons (kDa). It is encoded by the TRPA1 gene, which is found on chromosome 8, band q21.11, and contains 73635 bases and 29 exons (28). TRPA1 has an extended C- terminal domain, which is important for subunit interactions during channel assembly. The N-terminal region contains 16 ankyrin repeats and has a role in pore-gating and mediation of protein–protein interactions (35). There are 16 ankyrin repeat domains present in the cysteine-rich intracellular N-terminus of human TRPA1 (hTRPA1) subunits, and 14 ankyrin repeats are present in mouse TRPA1 subunits (35,36). TRPA1 activation occurs through covalent modification of N-terminal cysteines or lysines (6).

TRPA1 is a target for numerous products of oxidative stress (6,37) and activation has been shown to trigger the cough reflex in both animal and human models. TRPA1 also activates non-neuronal cells such as fibroblasts and airway smooth muscle cells which can play an important role in the cough response (6).

Numerous inflammatory mediators are endogenous TRPA1 agonists, including ROS, prostaglandins and bradykinin (38). The role of TRPA1 as a cough receptor may provide an important research gap for investigation in the sphere of lung cancer, particularly relating to the potential for earlier diagnosis, as coughing is one of the earliest and most common symptoms of lung cancer. There are currently limited studies which investigate the association between chronic cough and lung cancer (39).

Based on the numerous agonists of TRPA1 which exist in the environment, TRPA1 appears to play an important role in the detection of many harmful irritants (40). TRPA1 is also activated by noxious compounds such as allyl isothiocyanate (AITC) and formalin, and by other oxidizing compounds such as ozone or hydrogen peroxide (17). Cigarette smoke, which contains acrolein [a known agonist of TRPA1 (41)], has been shown to increase expression of TRPA1 in the A549 cell line (42). Other important activators of TRPA1 include oxidants generated in inflammatory states (43), which can lead to carcinogenesis.

Ion channel dysregulation has been shown to play a role in many disease processes, both inflammatory and neoplastic (23). Ion channels are critical for functions such as cellular proliferation, metabolism and apoptosis, and alterations in these cellular processes can be key drivers in oncogenesis (44). Cellular control of calcium, which is a major function of TRPA1, impacts downstream cellular signalling pathways that control apoptosis and cell migration (26), thus potentially leading to oncogenesis if dysregulated.

TRPA1 activation can induce apoptosis of numerous cell types including cardiomyocytes, oligodendrocytes and hippocampal neurons. Another TRP receptor, TPRV1, is activated by hypoxia in pulmonary artery smooth muscle cells and can also induce cell migration (19,45). These findings highlight some of the mechanisms by which ion channels, such as TRPA1, may be implicated in oncogenesis.

TRP channels and oncogenesis

Various TRP superfamily members, including TRPA1, have been implicated in the pathogenesis of a number of malignancies which include breast, colon, prostate, pancreatic ductal adenocarcinoma, SCLC, osteosarcoma, glioblastoma, gastric, oesophageal SCC and urothelial carcinoma (19).

Fels et al. (19) have also highlighted that TRP channels play a key role in the metastatic cascade. They described how calcium signalling aberrations, which are involved in multiple steps along the metastatic cascade, can impact key cellular functions such as cellular proliferation, apoptosis, metabolism, growth factor signalling, migration and invasion (19). Following ROS-induced cellular damage, TRPA1 can upregulate calcium dependent anti-apoptotic pathways to promote oxidative stress tolerance and cell survival (37), with retention of cellular DNA damage. This provides an oncogenic development pathway for cells.

Many TRP channels appear to be involved in tumour promotion, while others are involved in tumour suppression. For example, TRPV6 has been shown to be overexpressed in prostate cancer while TRPV1 is implicated in apoptotic pathways in some gynaecological cancers (40). In prostate cancer studies, TRPA1 has been shown to be overexpressed in prostatic tumour-derived endothelial cells (46). Upregulation of TRPA1 in these endothelial cells correlated with a higher migratory phenotype both in vitro and in vivo compared to their healthy counterparts (46,47), demonstrating a potential role in the development and spread of prostate cancer.

Indeed, TRPA1 has been implicated in the pathogenesis of prostate cancer according to a number of research studies. In a study by Vancauwenberghe et al., intracellular calcium concentrations increased (a key functional role of TRPA1) following treatment with Resveratrol, without inducing apoptosis, in a panel of prostate cancer cells (48). Other studies have also highlighted how TRPA1 can prevent apoptosis in prostate cancer cells (19). In prostate cancer stromal cells, TRPA1 activation leads to increased intracellular calcium, secretion of vascular endothelial growth factor (VEGF) and promotion of epithelial cell proliferation (49). TRPA1 activation has also been shown to promote metastasis and proliferation of prostate cancer cells (22,49).

Functional expression of TRPA1 has been confirmed in SCLC cell lines, which is in keeping with the established role of TRPA1 expression in neuronal/neuroendocrine cells. Due to expression of TRP channels on the plasma membrane and the existence of selective channel blockers or activators, these proteins may be accessible to targeted drug interventions in the future (40). This is another important research area for future consideration.

TRPA1 can accelerate metabolic processes in cancer cells that require high concentrations of ROS to maintain their elevated proliferation rates (25,50). In response to ROS, TRPA1 activation leads to intracellular calcium influx and avoidance of cellular apoptosis (25), thus promoting cancer cell survival.

Some studies have identified that TRPA1 may contribute to an invasive phenotype in lung cancer (51). TRPA1 can engage in anti-apoptotic survival mechanisms through calcium entry, or lead to cell apoptosis through mitochondrial calcium dysfunction (52). In a study by Schaefer et al., TRPA1 was expressed in a panel of SCLC cell lines where it played a potential role in cell survival (17), thus providing a link between TRPA1 expression and SCLC development.

Takahashi et al. (53) described how in breast and lung cancer, TRPA1 activation by ROS can lead to intracellular calcium alterations that may result in cell survival pathways being activated, such as toleration to oxidative stress (53). Therefore, TRPA1 may promote resistance to drug therapies that involve generation of ROS, such as carboplatin, doxorubicin and paclitaxel (53). In other solid organ malignancies, including glioblastoma and neuroblastoma, ROS-induced TRPA1 activation also resulted in a persistent increase in intracellular calcium, leading to apoptotic cell death (54). These findings demonstrate the role that TRPA1 may play in cell survival following oxidative stress, and the potential tumour resistance that could develop to therapies that rely on oxidative stress-induced apoptosis of cancer cells.

In a study of oral SCC by Kiss et al., TRPA1 was shown to be overexpressed in cancer cells (55). This study, which investigated functional TRPA1 expression in oral SCC using RNAscope in situ hybridization and quantitative polymerase chain reaction (qPCR), highlighted that TRPA1, normally expressed in the oral squamous epithelium, was significantly upregulated in oral SCC and that capsaicin-induced activation resulted in calcium influx into PE/CA-PJ41 (clone D2) cells (55). Therefore, not only was TRPA1 upregulated, but it was also functionally active in oral SCC.

Faris et al. (52) demonstrated that TRAP1 may play a key role in colorectal carcinoma development. They studied TRPA1 activation by ROS on primary cultures of metastatic colorectal carcinoma and highlighted that TRPA1, when activated by ROS, was upregulated and mediated enhanced calcium entry into metastatic colorectal cancer cells, when compared to non-neoplastic control cells (52). Zhang et al. also highlighted, using bioinformatics, that higher TRPA1 expression in colorectal cancer was associated with a poorer outcome (56). These studies provide important associations between TRPA1 expression and the development of colorectal carcinoma.

Mancini et al. (57) demonstrated the role of TRPA1 in pancreatic ductal adenocarcinoma, highlighting that TRPA1 contributes to fibroblast growth factor receptor 2 (FGFR2) enhancement of pancreatic ductal adenocarcinoma cell invasion. FGFR2 and TRPA1 interactions have already been established in lung cancer, with a direct TRPA1–FGFR2 interaction resulting in TRPA1 inhibition due to a conformational change in TRPA1 that subsequently induces the ligand-independent activation of FGFR2 and sustained proliferation and cell invasion (2,25,57). The TRPA1-FGFR2 interaction may therefore play a role in the development of both pancreatic ductal adenocarcinoma and lung cancer.

The impact of ion channel inhibitors on cellular mechanisms underlying lung cancer, such as proliferation, migration, invasion, cell cycle progression and adhesion, have been demonstrated by a number of studies (23). TRPA1 has been implicated in the pathogenesis of lung cancer (35,37,51,58,59), however this association is primarily in relation to SCLC. Studies relating to NSCLC are limited, and the evaluation of potential pathogenic roles needs to be developed further. The role of TRP channels, specifically TRPA1, in LUAD remains poorly understood (22,26).

This association is important to evaluate further as some TRP family members appear to have an effect on the sensitivity of tumours to platinum-based drugs, which are a key treatment modality in LUAD. This is not surprising since it is known that ion channels can affect chemotherapeutic drug sensitivity and resistance (23). TRPV1, for example, has been shown to confer resistance to cisplatin in one study by Oh et al., with subsequent inhibition of TRPV1 enhancing cervical cancer cell sensitivity to cisplatin (60). TRPC1, which has been shown to enhance cellular proliferation and migration in NSCLC (61), also conferred similar resistance to cisplatin in NSCLC cell lines, with inhibitors and knockdown of TRPC1 re-sensitising these cells to cisplatin (61). TRPA1 was shown to be activated by platinum-based drugs, promoting cellular oxidative stress defence processes in other studies (22,37). These findings suggest that some cancer cell resistance strategies against platinum-based chemotherapeutic agents may in part be mediated by ion channels, including those in the TRP superfamily. Such findings identify another important research gap in the realm of ion channels and lung cancer treatment, given the fact that significant therapeutic strategies in lung cancer involve platinum-based chemotherapeutic agents.

There is currently a paucity of information regarding TRPA1 expression in NSCLC. Given the recognised role of TRPA1 in the inflammatory milieu, anti-apoptotic cell survival mechanisms, other solid organ cancers and its vast presence throughout the respiratory system, there is a need to fully investigate its potential role in lung cancer development.

TRP channels and lung cancer

A limited number of studies have been published that provide a link between TRPA1 and lung cancer development, summarised in Table 1. Studies have linked other TRP channels, such as TRPC1, to the development NSCLC (61,63). Altered expression of TRPV4 may as well have a role in NSCLC development by promoting cancer growth (64) and angiogenesis (65). However, there is scant literature that specifically link LUAD and TRPA1. This represents an important research gap that has not been thoroughly investigated to date.

Feng et al. (62) were able to demonstrate, through investigation of tuberculosis and LUAD, that a tuberculosis-related pathogenic signature for LUAD exists, which includes Keratin 80 (KRT80), complement C1q tumour necrosis factor-related protein 6 (C1QTNF6), and TRPA1. These prognostically relevant markers were validated by reverse transcription quantitative real-time PCR (RT-qPCR) and single cell analysis (62). This remains one of the few published studies that has identified an association between TRPA1 expression and LUAD development.

Guo et al. (22) identified 15 TRP genes with prognostic significance in lung cancer using the Molecular Signatures Database TRP gene set and The Cancer Genome Atlas LUAD data collection. The 15 TRP genes studied using univariate Cox analysis were found to be prognostic in lung cancer (P<0.05). In Lewis lung cancer cells, expression of TRPA1 and TRPM8 were linked with autophagy, tumour cell metastasis, and energy metabolism, with higher expression of TRPA1 associated with poorer patient prognosis (22,51).

Schaefer et al. (17) aimed to analyse the expression patterns of TRP channels and their contribution to calcium signalling and cell survival in SCLC. They found that not only was TRPA1 overexpressed in SCLC cell lines, but that it prevented apoptosis induced by serum starvation and thus promoted cell survival (17). They also demonstrated that down-regulation of TRPA1 impaired the anchorage-independent growth capacity of SCLC cells (17).

Fels et al. conducted research investigating the roles of TRP channels in the metastatic cascade (19). They showed that methyl syringate, a TRPA1 agonist, inhibited induction of COX-2 and cell invasion of the A549 lung cancer cell line and the HT-1080 fibrosarcoma cell line under hypoxic conditions (19). TRPA1 has the ability to sense cellular hypoxic states, which can occur easily in tumour cells due to their high metabolic demands and which produce ROS that can exert pro-tumour or anti-tumour effects on cells. This study highlighted that TRPA1, which is a regulator of key steps in the metastatic cascade, can be activated by ROS produced in tumour-related hypoxic states (19).

Takahashi et al. identified that amongst the TRP channels, TRPA1 was the most highly upregulated in lung SCC and was the second most highly upregulated in LUAD (53), which is a significant finding. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 was critical for the survival of inner cells that exhibited ROS accumulation (53). It was also demonstrated that cancer cells were able to utilise TRPA1 functionality as a method of oxidative stress tolerance and cell survival (37). TRPA1 was shown to be able to sense ROS and upregulate calcium dependent anti-apoptotic pathways that promote oxidative stress tolerance (37). Therefore, not only was TRPA1 upregulated in these cancers but its expression also appeared to confer cell survival benefits to these tumours.

Despite these well-structured studies, the role of TRPA1 in NSCLC, particularly LUAD, has not yet been fully evaluated and more research is required to investigate its potential role in pathogenic, prognostic and resistance mechanisms of this malignancy.

TRPA1 and LUAD

There is limited published research that has been able to demonstrate the potential role of TRPA1 in the pathogenesis of LUAD.

FGFR2 has been shown to drive LUAD progression in a number of studies. TRPA1 can both bind and activate FGFR2, revealing a potential pathway in LUAD development and progression through a TRPA1-FGFR2 oncogenic interaction (35). This interaction functions by FGFR2 recruiting proteins to a proline-rich motif at the C-terminus of TRPA1, resulting in receptor phosphorylation and activation of downstream signalling pathways that can promote LUAD progression (25,35).

Berrout et al. (2) also demonstrated that the FGFR2 can lead to LUAD progression through these same aberrant protein-protein interactions, mediated via its C-terminal proline-rich motif. The N-terminal ankyrin repeats of TRPA1 were shown to directly bind to the C-terminal proline-rich motif of FGFR2, which lead to activation of the receptor and promotion of LUAD progression and metastasis. This study revealed a direct binding event between ankyrins 6–10 of TRPA1 and prolines 810–813 of FGFR2, which activated the receptor and its signalling pathways independent of extracellular stimulation (2). These studies suggest that the FGFR2-TRPA1 interaction may be one of the key pathogenic events that implicates TRPA1 and LUAD development.

Sakamoto et al. (41) demonstrated that overexpression of TRPA1 in A549 lung cancer cells increased acrolein sensitivity, and that knockdown of TRPA1 in A549 cells or treatment with a TRPA1 antagonist resulted in tolerance to acrolein. They suggested that increased TRPA1 expression also increased the cytotoxicity of acrolein (41). These findings are of interest as acrolein is a key chemical in cigarette smoke and thus may demonstrate how TRPA1 is implicated in the pathogenesis of cigarette smoke-related LUAD development.

Recent in silico analyses have indicated that TRPA1 messenger ribonucleic acid (mRNA) is upregulated in both in lung SCC and LUAD (66). Moreover, TRPA1 expression showed a positive correlation with higher lung cancer stages and risk of metastasis (66). These in silico findings linking TRPA1 mRNA expression with LUAD and lung SCC warrant further investigation in the in vitro setting, especially given the fact that targeted therapies against TRPA1 are in development, primarily in the inflammatory lung disease milieu.

Although there are limited studies specifically investigating the potential role of TRPA1 in lung cancer, TRPA1 does have a well-recognised role in inflammatory lung disease development.

TRPA1 and inflammatory lung diseases

TRPA1, which is highly expressed throughout the airways and lungs, has been linked to a number of inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) (67) and pulmonary fibrosis [given its recognised expression in lung fibroblasts (28)]. Its role in inflammatory lung diseases primarily occurs though the regulation of intracellular calcium, which controls cell proliferation, differentiation, apoptosis and autophagy. The actions of TRPA1 as an inflammatory gatekeeper (68) and sensor of ROS is crucial to these pathways.

Asthma is a chronic inflammatory condition with an increasing prevalence worldwide, closely linked to environmental changes (69). Selective inhibition of TRPA1 has been shown to reduce pulmonary inflammation and airway hyperreactivity in asthma models in mice and guinea pigs (43). First generation TRPA1 inhibitors (TRPA1i) were also shown to reduce airway inflammation and hyperreactivity in mouse and guinea pig models in allergic asthma (43,70). Expression of TRPA1, along with TRPV1, was upregulated in asthmatic mice (69) and played a key role in asthma exacerbations. The role of TRPA1 in asthma has therefore been well established to date.

Inflammatory regulation is a key function of TRPA1 (14). Low expression of TRPA1 was identified in A549 lung cancer cell lines in the absence of inflammatory stimuli; however, tumour necrosis factor (TNF)-alpha significantly increased TRPA1 expression in this cell line (14). TRPA1 was therefore found to be expressed and functional in A549 cells under inflammatory conditions (14). Fibroblast cell lines MRC-5 and HF19, when stimulated with TNF-alpha, also showed upregulation of TRPA1 mRNA expression (71), and the upregulation of TRPA1 was associated with the release of further inflammatory cytokines (71). This evidence supports the hypothesis that TRPA1 can have a significant role in the pathogenesis of pulmonary inflammatory conditions.

Further work is now required to investigate the role of TRPA1 in the pathogenesis of lung cancer. However, certain limitations exist in the laboratory setting regarding TRPA1 detection in human tissue samples, which could potentially limit research in this area.

Limitations to the detection of TRPA1 in human tissue

The use of appropriately validated antibodies is essential in laboratory research. This has proven problematic in the analysis of TRPA1, as thorough antibody validation data has often been omitted in studies using TRPA1 antibodies. This introduces the possibility of reactivity with other antigens (30) and may therefore limit the validity and reproducibility of such work.

The main limitations that exist relate to the ability to detect TRPA1 protein expression in human tissue using immunohistochemistry. Antibody based techniques are commonly used for this purpose, however there is currently no available antibody with appropriate validation in knockout animals of functional studies for TRPA1 (32). Due to low antibody specificity, antibody-based detection methods have proven difficult in both western blots and immunohistochemistry (30,32).

Despite this, other detection techniques have been attempted to confirm the functional expression of TRPA1 in human tissue. One such technique has utilised single molecule in-situ hybridisation (RNAScope) on sensory neurons directly following the detection of a calcium response to a known TRPA1 agonist, which successfully showed a positive correlation between TRPA1 calcium imaging and RNAScope detection (32). Functional validation was performed in this case, as a key limitation of RNA in-situ hybridisation is the potential discordance between mRNA and functional protein expression. Of note, this study highlighted issues with antibody detection ability and specificity in human TRPA1 (32).

As of 2019, the majority of antibodies to human TRPA1 have demonstrated poor reproducibility (30,32), and to our knowledge this situation has not significantly improved to date. Rigorous antibody validation for human TRPA1 is currently scant throughout scientific literature (30). Virk et al. studied the expression profile of TRPA1 in human lung and airway cell lines (30) and sought to evaluate 5 commercially available TRPA1 antibodies in a panel of cell lines by western blotting, immunofluorescence, immunocytochemistry and flow cytometry. They found that the 3 most cited antibodies all lacked appropriate specificity and/or sensitivity. However, 2 mouse monoclonal TRPA1 antibodies detected human TRPA1 in the assays (30). These 2 mouse antibodies were specific for TRPA1 by western blotting and demonstrated good specificity for human TRPA1 in transfected human embryonic kidney (HEK)-293-cells (30). It appears that the use of immunohistochemistry to detect TRPA1 in human tissue remains problematic due to an overall lack of appropriate sensitivity and specificity. RNAScope in conjunction with functional analysis by calcium signalling (32) may be the best option to confirm TRPA1 functional expression in human tissue until a fully validated antibody becomes commercially available.

Therapeutic TRPA1 candidates for treatment of pain and/or cancer

Due to the established role of TRPA1 in inflammatory lung diseases, several therapeutic candidates have been trialled as TRPA1i with varying success. A study by Broad et al. (72) concluded that LY3526318 a selective and orally bioavailable TRPA1 antagonist, blocked TRPA1 both in vitro and in vivo, inhibited behavioural signs of nociception in animal models, and was well tolerated in phase 1 clinical studies. This agent was therefore deemed to display a pharmacokinetic profile suitable for advancement to proof-of-concept studies in patients with chronic pain (72). Initial results of these trials (ClinicalTrials.gov NCT05080660; NCT05177094 and NCT05086289) have recently been reported and whilst this drug was able to clearly demonstrate its ability to manage pain, different responses were observed amongst the different chronic pain conditions tested and/or between patient subpopulations highlighting potential challenges associated with developing TRPA1 targeting agents (73).

Shirai et al. also demonstrated that a TRPA1i originating from perfumery compounds could be successfully formulated for topical and aerosol delivery against inflammatory symptoms such as itch and skin irritation (29). A potent and highly selective TRPA1i, 2-methyl-4-phenyl-1-pentanol, demonstrated inhibitory activity in HEK-293-cells overexpressing human TRPA1. This compound also demonstrated inhibitory activity against a broad range of TRPA1 agonists, including cinnamaldehyde (29). The possibility of a topical or aerosolised inhibitor of TRPA1 is an interesting area for further research given the emerging interest of TRPA1 in both inflammatory and neoplastic diseases. TRPA1 has a significant role in the detection of pain, itch and inflammation in the skin and airways (29) and is highly expressed in nociceptive neurons (74), increasing interest in this receptor as a target in asthma, COPD and allergic skin diseases.

Despite these promising findings, several drug candidates which were initially trialled have since been discontinued due to issues surrounding drug pharmacokinetics. Phase 1 and 2 trials are currently in progress for TRPA1 antagonists for the treatment of cough and neuropathic pain (32). Preti et al. (74) and Hu et al. (75) have recently completed comprehensive reviews regarding the developmental status of small molecule inhibitors of TRPA1. These reviews highlighted that the TRPA1 antagonist, GRC-17536, demonstrated efficacy in the management of diabetic neuropathic pain in phase 2A proof of concept studies (74,75). Animal studies have also highlighted that the efficacy of TRPA1i may extend beyond pain management to also include the treatment of inflammatory conditions like asthma and COPD (74). A key issue in the progression of TRPA1i in clinical trials is the identification of high quality orally (or topical and aerosolised) bioavailable molecules, as many ligands are unsuitable for clinical progression due to low lipophilic efficiency, poor absorption, distribution, metabolic, excretion and pharmaceutical properties (76). This can be exemplified by the fact that from the years 2015–2019, 28 patent applications were filed (77), bringing the number of TRPA1 antagonists to reach clinical trials up to five. However, development of all five molecules have been discontinued (77).

Balestrini et al. (78) did identify a highly selective and orally bioavailable TRPA1i, GDC-0334, which inhibited TRPA1 function in airway smooth muscle cells and sensory neurons. In a healthy volunteer Phase 1 study, treatment with this agent reduced agonist-induced dermal blood flow, pain and itch (78,79).

TRPA1 has a role in the sensation of pain (80) and may therefore be a potential target in the management of numerous nociceptive conditions, including neuropathic, inflammatory and migraine pain (30). Do et al. identified a novel TRPA1/TRPV1 antagonist which appears to have potential therapeutic efficacy in pain management (80). Some analgesic and anti-migraine drugs have also been shown to inhibit or desensitize TRPA1 (81).

Bamps et al. (82) demonstrated that cinnamaldehyde-induced alterations in dermal blood flow could be used as a target engagement biomarker for TRPA1 activity. They also showed that the compound LY3526318 demonstrated antagonistic activity to TRPA1 in both rats and humans (82). Despite a low number of TRPA1i reaching clinical trials, a number of compounds have so far reached Phase 2 trials: GRC-17536 for diabetic peripheral neuropathy and LY3526318 for chronic lower back pain and diabetic peripheral neuropathy. Another compound, DC-6599, has also entered Phase 2 trials for the management of chronic cough (83). To our knowledge, TRPA1 drug candidates are not yet in development for the management of lung cancer, as further work is required to fully evaluate the role of TRPA1 in this regard.

Role of TRPA1 in e-cigarettes

TRPA1 is activated by acrolein, a chemical produced in cigarette smoke. Smoking is widely implicated in the pathogenesis of numerous respiratory diseases, including lung cancer. However, electronic (E) cigarette flavouring has also been shown to have detrimental health effects in vitro and in vivo, which include apoptosis and airway inflammation (84). A significant body of research has been undertaken to investigate the role of TRPA1 in the inflammatory milieu and in addition, its potential activation by the use of e-cigarettes (13). In this study Effah et al. (13) observed that three e-cigarette liquids had significant dose dependent toxic effects on HBEC-3KT cells. Exposure to e-liquid flavoured compounds can result in adverse effects on pulmonary epithelial cells which include generation of ROS, growth inhibition, cytotoxicity and mitochondrial dysfunction.

Cinnamaldehyde, the primary chemical constituent of cinnamon flavour, is a known TRPA1 agonist (13,67). Cinnamon is one of the most toxic flavours utilised in e-cigarettes. Through quantification of TRPA1 mRNA levels, it was shown that 1% cinnamon e-liquid significantly increased TRPA1 expression in HBEC-3KT cells (human bronchial epithelial cells), which are known to functionally express TRPA1 (13,16). Cinnamon was identified as being amongst the most toxic flavours encountered in e-cigarettes, with further research demonstrating negative effects by increasing lactate dehydrogenase (LDH) release and eliciting a dose dependent reduction on cell viability (13). It has been suggested that TRPA1 expression in lung tissue confers protective effects against noxious xenobiotics and helps to induce inflammation by recruiting immune cells, thereby protecting cells against the potential damage caused by cinnamon exposure. However, it is important to note is that the upregulation of TRPA1 mRNA by cinnamaldehyde may not necessarily result in TRPA1 protein expression (13).

Use of e-cigarettes was also shown to result in airway mucociliary dysfunction in one study, with nicotine’s primary effect on mucociliary dysfunction suggested to be mediated by TRPA1 as opposed to nicotine acetylcholine receptors (84). Cheng et al. found that nicotine preferentially stimulated TRPA1 channels, with inhibition of TRPA1 preventing the detrimental effects on mucociliary clearance both in vitro and in vivo (84). These studies highlight that respiratory diseases mediated by TRPA1 may be activated not only by conventional cigarette smoking, but also by use of e-cigarettes.

Is epigenetic regulation of TRPA1 involved in lung cancer development?

TRPA1 has been shown to be expressed in the LUAD cell line A549. One important question relating to potential TRPA1 expression in lung cancer is the role of epigenetic regulation. The heterogenous expression of genes mostly arises during embryonic development. These changes are termed epigenetic since they are heritable and do not necessarily involve acquired DNA mutations (85). Two of the key mechanisms that lead to epigenetic changes relate to DNA methylation and histone modifications. Epigenetic changes that arise due to DNA methylation can occur as organisms age. External factors may also influence epigenetic changes (85).

TRPA1 is subject to epigenetic modifications, and this has an impact on its functionality. A methylation analysis study on monozygotic twins identified that methylation of a CpG (5'-C-phosphate-G-3') dinucleotide in the promoter region of TRPA1 was inversely related to the heat-induced pain sensation. This CpG site was also found to be hypermethylated in subjects with a lower threshold for pressure pain, supporting the hypothesis that epigenetic regulation of TRPA1 influences thermal and mechanical pain sensitivities (86). A systematic review investigating the role of TRPA1 methylation patterns and chronic pain concluded that TRPA1 hypermethylation and increased pain sensitivity may be related, possibly due to TRPA1 variation (87). Further studies highlighted that neuropathic pain characteristics were likely associated with promoter region methylation of TRPA1 (88).

Unfortunately, there appears to be limited scientific evidence regarding epigenetic changes of TRPA1 and the development of cancer. This appears to be a literature gap that needs to be addressed, given the role that TRPA1 epigenetic changes, particularly hypermethylation, appear to have in the inflammatory and pain settings. One study has identified, using bioinformatic analysis, that TRPA1 appears hypermethylated in a number of cancer types (66). Using the University of Alabama at Birmingham cancer data analysis portal (UALCAN), the promoter region of TRPA1 appeared hypermethylated in comparison to a number of non-tumoural samples. Through this study, epigenetic changes such as DNA hypermethylation were attributed with modulating the expression of TRPA1 (66). Given the role of TRPA1 in the development of various cancers, the role of TRPA1 hypermethylation is another research gap that warrants investigation.

Conclusions

TRPA1 is a nonselective ion channel, with high permeability for calcium, that is involved in numerous physiological functions (28), including thermoregulation, nociception, phagocytosis, cell motility and inflammatory pain sensation (19,29). Its roles in inflammatory conditions of the respiratory tract have been well established. TRPA1 influences acute and chronic inflammatory processes, has been linked to both asthma and COPD and may have a role in pulmonary fibrosis progression (28), with inflammatory regulation being a key function of TRPA1. Its upregulation with e-cigarette usage, particularly with the cinnamaldehyde flavour, is another area of interest in the inflammatory milieu.

TRPA1 has been implicated in a variety of cancers, and interest in its role in the oncology setting is expanding. The potential roles of TRPA1 extend to involvement in the metastatic cascade (19), activation by platinum-based drugs to promote cellular oxidative stress defence processes (22,37), functional expression in SCLC, accelerated metabolism in cancer cells that require high concentrations of ROS to maintain high proliferation rates (25,50), avoidance of cellular apoptosis to promote cancer cell survival (25) and its implication in the pathogenesis of prostate cancer, breast cancer, oral SCC, colorectal carcinoma and PDAC (through a TRPA1-FGFR2 interaction).

The role of TRPA1 in lung cancer has yet to be fully investigated. Involvement in SCLC and SCC has been demonstrated by a number of studies, however limited information regarding a potential role in LUAD development exists. Preliminary studies have shown that FGFR2 may drive LUAD progression and that TRPA1 can bind and activate FGFR2 in this regard. Other studies have highlighted that overexpression of TRPA1 in A549 lung cancer cells increased acrolein sensitivity, therefore potentially promoting acrolein mediated cytotoxicity (37). This represents a research gap which should be investigated, based on promising in silico data which suggests a significant relationship between TRPA1 expression in NSCLC and higher stage of disease spread/metastasis (66).

In terms of conducting TRPA1 in vitro studies, there are limitations in the ability to detect TRPA1 in human tissue, as antibody validation for TRPA1 is not at a sufficiently appropriate level to ensure high sensitivity and specificity (32). Other techniques such as the combination of calcium imaging and RNAScope detection may be sufficient, until a validated antibody becomes commercially available.

Several therapeutic candidates have been trialled as TRPA1i, with Phase 1 and 2 trials in progress for the treatment of cough and neuropathic pain (32). Two compounds have reached Phase 2 trials: GRC17536 for diabetic peripheral neuropathy and LY3526318 for chronic lower back pain and diabetic peripheral neuropathy. Another compound, DC-6599, has recently entered Phase 2 trials for the management of chronic cough (67).

TRPA1 represents a potentially targetable protein with a role in both inflammatory and neoplastic conditions throughout the body, but particularly in the airways and lungs given its extensive expression in the respiratory system. Research on the potential role of TRPA1 in the LUAD setting, despite very promising in silico data and its demonstrated role in other cancer types, is lacking. This represents an important research gap which should be addressed.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-114/prf

Funding: This work was supported by Breakthrough Cancer Research (Innovation_005_2024 to D.O. and S.G.G.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-114/coif). S.P.F. reports consulting fees from Roche, Takeda and Illumina; honoraria from Astra Zeneca, Johnson & Johnson and Amgen; and support for attending meetings and/or travel from Pfizer and Johnson & Johnson. S.G.G. and D.O. received research funding support from Breakthrough Cancer research Ireland (Grant Number: Innovation_005_2024: Title “Investigating the role of TRPA1 in lung cancer”). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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