Insights into the leveraging of GABAergic signaling in cancer therapy

Abstract Gamma‐aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain of adult mammals. Several studies have demonstrated that the GABAergic system may regulate tumor development via GABA receptors, downstream cyclic adenosine monophosphate (cAMP) pathway, epithelial growth factor receptor (EGFR) pathway, AKT pathway, mitogen‐activated protein kinase (MAPK) or extracellular signal‐related kinases (ERK) pathway, and matrix metalloproteinase (MMP) pathway, although the exact mechanism is unclear. Pioneering studies reported that GABA signaling exists and functions in the cancer microenvironment and has an immunosuppressive effect that contributes to metastasis and colonization. This article reviews the molecular structures and biological functions of GABAergic components correlated with carcinogenesis, the mechanisms underlying GABAergic signaling that manipulate the proliferation and invasion of cancer cells, and the potential GABA receptor agonists and antagonists for cancer therapy. These molecules may provide an avenue for the development of specific pharmacological components to prevent the growth and metastasis of various cancers.


| THE GABAergic SYSTEM
The GABAergic system functions as an inhibitory neurotransmitter in the CNS and mainly contains GABA, GABA transporters, GABA receptors, and GABAergic neurons. 24 In GABAergic neurons, GABA can be directly synthesized by the decarboxylation of glutamate in the cytosol. 25 Alternatively, GABA can be indirectly formed from glutamate by bypassing the tricarboxylic acid (TCA) cycle. This process is called the GABA shunt, a closed-loop system in charge of the production and conservation of GABA supply 25 (Figure 1). GABA synthesis is mediated by two GAD isoforms, namely, GAD65 and GAD67. GAD65 mainly participates in GABAergic synaptic transmission and plasticity, whereas GAD67 manipulates metabolic GABA synthesis. 26 Notably, GAD67 is upregulated in tumors and contributes to cancer progression, whereas GAD65 remains unreported. 27 GAD67 facilitates tumor progression as it is overexpressed in tumor tissues with greater proliferative and invasive potential. [28][29][30] Moreover, high DNA hypermethylation, mRNA expression, and protein expression F I G U R E 1 The schematic diagram of GABA synthesis and the potential mechanisms of GABAergic components in cancer proliferation and invasion. In cancer cells, GABA is formed from glutamate directly or via TCA cycle metabolism, and high level of GABA in the tumor microenvironment due to increased GABA production from GAD and decreased GABA degradation by ABAT. Then the synthesized GABA activates the GABA receptors by combining with the extracellular binding domains of GABA A receptors or GABA B receptors to regulate cancer cell proliferation and/or invasion. ABAT, 4-aminobutyrate aminotransferase; cAMP; cyclic adenosine monophosphate; EGFR, epithelial growth factor receptor; GABA, gamma-aminobutyric acid; GAD, glutamic acid decarboxylase enzyme; MAPK/ERK, mitogenactivated protein kinase/extracellular signal-related kinase; MMP, matrix metalloproteinase; TCA, tricarboxylic acid. of GAD67 have been correlated with advanced tumor status, which makes it a potentially important prognostic indicator of poor outcomes in several cancer types. 27,[31][32][33] The GABA transaminase 4-aminobutyrate aminotransferase (ABAT) catabolizes GABA into succinic semialdehyde. Reduced expression of ABAT in some cancer cells may promote cancer cell proliferation and migration due to the accumulation of GABA. [34][35][36] Therefore, the inhibition of GAD67 expression and promotion of ABAT expression may reduce cancer progression.
GABA functions via two types of receptors, namely, ionotropic GABA A and GABA C receptors and metabotropic GABA B receptors, which have different structures and functions ( Figure 2). GABA A receptors (GABA A R) are members of ligand-gated chloride channels families consisting of the assembly of multiple subunit subtypes (α1-6, β1-3, γ1-3, δ, ϵ, θ, π, ρ1-3) into a pentamer. The pharmacological and functional properties of GABA A R channels closely depend on their subunit composition. The most abundant GABA A R subtype consists of two α, two β, and one γ subunits. 37 GABA A R is activated by binding with GABA to open the Cl − channel, subsequently inducing the hyperpolarization of the postsynaptic membrane. Contrary to GABA-binding sites, GABA A R possesses several allosteric binding sites for anxiolytic, hypnotic, anesthetic, and anticonvulsant drugs. 38 For instance, bicuculline and picrotoxin are antagonists of GABA A R, whereas propofol and benzodiazepines are its agonists. 39-41 GABA B receptors (GABA B R) are members of the family of heterodimeric G-protein-coupled receptors, which are composed of two main GABA B R subunits termed GABA B receptor 1 (GABA B R 1 ) subunit and GABA B R 2 subunit. 42 Each subunit contains a C-terminal intracellular domain, an N-terminal extracellular domain, a heptahelical transmembrane domain, and an extracellular Venus flytrap domain. The subunits interact with each other via an intracellular coiled-coil domain near the C terminus, which can mask the reticulum retention signal. GABA B R can be activated by GABA to regulate Ca 2+ channels and K + channels. 43,44 GABA activates serious proteins connecting with the C-termini of GABA B R by binding with the extracellular domain of GABA B R 1 , whereas the extracellular domain of GABA B R 2 has no ligand-binding activity. Some allosteric modulators, such as CGP7930, can bind the transmembrane domain of GABA B R 2 to modulate the binding affinity of the ligand with GABA B R 1 , as well as the efficacy of signal transduction after binding. 45 However, the mechanisms governing downstream signaling remain unclear.
All components of the GABAergic system have also been reported to be highly expressed in peripheral organs such as the liver, 46 pancreas, 47,48 prostate, 49 kidneys, 50 intestines, 51 testes, 52 and ovaries, 53 thus highlighting the pivotal effect of the GABAergic system in human development.

| The effects of GABA and its receptors in different cancers
Recent studies have demonstrated that GABA exerts crucial regulatory effects on various types of cancers by F I G U R E 2 GABA A receptor and GABA B receptor molecular and functional structure. (A) GABA A R is a pentameric ligand-gated ion chloride channels consisting of five transmembrane subunits. The most abundant GABA A R subtype consists of 2α, 2β, and 1γ subunits. GABA A R is activated by binding with GABA to open Cl − channel. (B) GABA B R is a heterodimeric G-protein-coupled receptor composed of the GABA B R 1 subunit and GABA B R 2 subunit. The subunits interact with each other via intracellular coiled-coil domains near the C terminus. The intracellular loops of GABA B R 2 are coupled to Gi/o-type G-proteins. The extracellular domain of GABA B R 1 can bind GABA, whereas the extracellular domain of GABA B R 2 has no ligand-binding activity. GABA B R is activated by binding with GABA to regulate K + channels and Ca 2+ channels. GABA A R, GABA A receptor; GABA B R, GABA B receptor; GABA B R 1 , GABA B receptor 1; GABA B R 2 , GABA B receptor 2.
binding with its receptors. In most cases, the expression levels of GABA and its receptors showed significant changes in tumor tissues compared with normal tissues, with GABA affecting cellular proliferation through GABA A R and cellular invasion through GABA B R. However, it is unclear as to whether GABAergic signaling could serve a positive or negative role in the regulation of cancer cell behavior (Table 1). GABAergic signaling may have different functions that depend on the origin of the tumor and the type of receptor subunits, which underscore the need to understand the GABA crosstalk in cancer.

| The effects of GABA on cancers
The GABA pathway plays a dual role and can be differentially regulated in different cell populations. GABA promotes tumor development in prostate cancer, 18,22,54 gastric cancer, 23 ovarian cancer, 55 and oral squamous cell carcinoma (OSCC). 56 In contrast, GABA exerts inhibitory effects on non-small cell lung cancer (NSCLC), 57 pulmonary adenocarcinoma (PAC), 58 colon cancer, 59 and cholangiocarcinoma. 60 Notably, GABA and its receptors have a dual function in hepatocellular carcinoma (HCC), 17,61-63 pancreatic ductal adenocarcinoma (PDAC), 30,64 and breast cancer. [65][66][67][68] In HCC, Li et al 17 found that GABA promotes the proliferation of hepatoma cells through the GABA A R θ subunit (GABA A R Q ), while Yan et al 61 found that this effect occurs through the GABA A R α3 subunit (GABA A R A3 ). However, other subunits of GABA receptors may play an opposite role. Minuk et al 62 30 and OSCC, 56 and inhibit cell proliferation through the GABA A R in cancers such as HCC 62 and cholangiocarcinoma. 60 The GABA A R Q and GABA A R A3 subunits of GABA A R, which mediate inhibitory synaptic transmission in the CNS, were overexpressed in HCC tissues compared with adjacent nontumor liver tissues, and the knockdown of GABA A R Q and GABA A R A3 expression in malignant hepatocytes resulted in attenuated tumor growth both in vitro and in vivo. 17,61 In contrast, GABA A R B3 exerts an opposite function. 62 The overexpression of GABA A R A3 also promoted the migration, invasion, and metastasis of breast cancer cells. 68 GABA A R P , a subunit of GABA A R, has been reported to promote tumorigenesis, proliferation, and migration of PDAC cells, basal-like breast cancer, ovarian cancer, and OSCC, 30,55,56,67 which confirms the function of GABA A R P in the initiation and progression of cancer. In human thyroid cancer, the expression of GABA receptors was higher in tumors than in normal thyroid tissue, and GABA A R appeared to play a vital role. GABA A R B2 was detected in the blood vessels of normal thyroid and thyroid tumors but not in thyroid cancer cells, suggesting that GABA signaling contributes to angiogenesis in thyroid cancer. GABA A R A2 was detected in metastasis-derived but not in primary-tumor-derived cell lines, suggesting its possible role in the development of metastases. 69 Although the research by Roberts documents the expression of the GABAergic system in human thyroid tumors, further functional studies are needed.
3.1.3 | The effect of GABA B receptors on cancers GABA B R plays a positive role in cancer cell invasion in breast cancer 65 and prostate cancer 22 and a negative role in breast cancer, 66 colon carcinoma, 59 NSCLC, 57 HCC, 63 and cholangiocarcinoma. 60 GABA B R 1e is overexpressed in human breast cancer cell lines and tissues and promotes the malignancy of breast cancer cells both in vitro and in vivo. 65 The expression of the GABA receptor gene phenotype is associated with tumorigenesis and the clinical prognosis of NSCLC. A high expression of GABA B R 2 with a low expression of GABA A R A3 may predict a better outcome. 57 The diverse roles of GABA and its receptors need further description, which would yield more insights into novel drugs for treating cancers by targeting the regulation of GABAergic signaling. Ongoing efforts to characterize the mechanisms of GABA A R and GABA B R in cancers have revealed the potential downstream pathways of GABA receptors.

| The mechanisms of GABAergic signaling in cancer progression and metastasis
GABAergic signaling contributes to tumorigenesis in systemic organs, and growing evidence has elucidated the potential pathways of tumor progression and metastasis. Moreover, the GABAergic system has recently been shown to exert immunosuppressive effects by disrupting the functions of various peripheral immune cells ( Figure 1).

| cAMP pathway
Cyclic adenosine monophosphate (cAMP) signaling can regulate the biological behavior, including proliferation, migration, invasion, and metabolism, of cancer cells. Notably, cAMP signaling can either promote or suppress tumors depending on the cell type and the specific environment. 70 Current reports have reported that cAMP plays a pivotal role in the inhibitory effect of GABA on tumors. GABA can suppress the proliferation and migration of NSCLC, PAC, and cholangiocarcinoma cells via cAMP signaling. 57,58,60 Similarly, GABA can also inhibit colon cancer and HCC migration mediated by GABA B R and intracellularly transduced by a decrease in the cAMP concentration. 19,59,63 Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients. Zhou et al 71 first described that the downregulation of GABA B R contributed to the development and maintenance of CIBP, and the restoration of depleted GABA B R attenuated CIBP-induced pain behaviors at least partially by inhibiting the cAMP signaling pathway. Moreover, baclofen significantly inhibited mechanical allodynia and ambulatory pain induced by CIBP in a dose-dependent manner.

| EGFR pathway
The epithelial growth factor receptor (EGFR) family has been widely researched in pharmacology owing to its close association with malignant proliferation. 72 GABA A R can be activated by 5α-androstane-3α,17β-diol (3α-diol) in prostate cancer cells to transform androgen-dependent EGFR pathways for the progression of castration-resistant prostate cancer. 73 Moreover, Wu et al 54 demonstrated that increased GABA A R A1 might participate in this tumorpromoting action by activating EGFR and the downstream signaling molecule Src. GABA B R can also transactivate EGFR through a ligand-dependent mechanism, thus promoting the migration and invasion of prostate cancer cells. 74 Furthermore, the GABA B R agonist baclofen selectively causes multisite phosphorylation of tyrosine residues associated with EGFR ubiquitination. 74 Further the research group 65 describes that GABA B R 1e favors EGFR signaling by displacing phosphatase nonreceptor type 12 (PTPN12) to disrupt the interaction between EGFR and PTPN12, which in turn promotes the growth and invasion of breast cancer cells.

| AKT pathway
AKT is a serine/threonine kinase that participates in the critical role of the PI3K signaling pathway, which regulates the survival, invasion, migration, and epithelialmesenchymal transition (EMT) of cells. The kinase activity of AKT is induced by various growth factors, including EGFR, while the translocation of AKT from the cytoplasm to the inner surface of the cell membrane, a key process of AKT phosphorylation, depends on PI3K-generated phospholipids. GABA may trigger several signaling molecules upstream of AKT to influence carcinogenesis through AKT signaling. Although GABA A R has been shown to regulate EGFR activation in prostate cancer, this condition was not observed in breast cancer cells. The overexpression of GAB A R A3 promotes the migration and metastasis of breast cancer through AKT signaling. 68 GAB A R A3 may mediate signaling molecules upstream of the AKT pathway, like PI3K, rather than EGFR. Conversely, GABA B R can mediate the EGFR-AKT signaling pathway. Moreover, in breast cancer, GABA B R 1e can activate the EGFR-AKT pathway to promote the malignancy of breast cancer cells both in vitro and in vivo. 65 Similarly, GABA enhances the malignancy of human high-grade chondrosarcoma by promoting AKT signaling. 75

| MAPK/ERK pathway
Mitogen-activated protein kinases (MAPKs) or extracellular signal-related kinases (ERKs) are serine/ threonine kinases that transform extracellular stimuli into intracellular signals controlling cell proliferation and differentiation, and their dysregulation induces tumorigenesis. 76,77 Elevated intracellular Ca 2+ , induced by GABA to influence neurogenesis and synaptogenesis, activates the small guanine nucleotide-binding protein Ras and stimulates the MAPK cascade. 78 GABA A R, particularly GABA A R P , contributes to the proliferative and aggressive action of advanced tumors by activating MAPK/ERK signaling. GABA stimulates tumor growth in PDAC, basal-like breast cancer, and ovarian cancer through GABA A R P by activating the MAPK/ERK cascade by increasing intracellular Ca 2+ levels. 30,55,67 Similarly, GABA A R P promotes the proliferation of OSCC by activating the MAPK pathway. 56 GABA can also promote the growth of human gastric cancer cells in an autocrine or paracrine approach through GABA A R, followed by the activation of MAPK/ERK and an increase in cyclin D1. 23 Besides GABA A R, GABA B R can also facilitate the invasion and metastasis of breast cancer mediated by promoting the phosphorylation of ERK1/2 and subsequently increasing the expression of MMP-2. 79 The MAPK/ERK pathway also involves the tumor-suppressive effect of GABA. GABA decreases the in vitro cholangiocarcinoma growth through protein kinase A-and D-myo-inositol-1,4,5-triphosphate/Ca 2+ -dependent pathways followed by the downregulation of ERK-1/2 phosphorylation and cAMP. 60

| MMP pathway
Matrix metalloproteinases (MMPs) are critical to tumor invasion and metastasis, as they influence the shape, movement, growth, survival, and differentiation of cancer cells by mediating the cytoskeletal machinery and cell adhesion. 80 The overexpression of GAD1 is closely correlated with the invasion and metastasis of OSCC by the activation of MMP7. 81 GABA promotes the invasion of prostate and breast cancer cells through GABA B R, and the increasing activities of MMPs, especially MMP-2 and MMP-3, are involved in the mechanism underlying this function. 18,79 Moreover, the MMP inhibitor GM6001 can significantly decrease GABA-induced migration, 18 with MMPs also being involved in the inhibitory effect of GABA in cancers such as colon cancer. Nembutal, a GABA agonist, inhibits the primary growth and metastasis of colon cancer, as it can reduce MMP production. 19 Owing to the involvement of a complex cascade of events in cancer progression and metastasis, the above signaling pathways are intricately intertwined rather than independent of each other. Existing evidence has demonstrated that the activation of GABA B R downregulates the phosphorylation of ERK1/2 via the cAMP/ PKA-dependent pathway 60 and consequently promotes the production of MMPs. 79 GABA B R can reduce the activity of adenylyl cyclase and enhance the production of cAMP due to its association with G i and G o. 82 Moreover, EGFR transactivated by GABA B R induces the activation of ERK1/2 by a G i/o -dependent mechanism that requires MMP-modulated pro-ligand shedding. 74 Further details about the modulatory mechanism need further clarification.

| Cancer microenvironment
The GABAergic system is highly expressed in peripheral organs, and its control over the biological behavior of cells is also widespread through peripheral organs not only limited the CNS. The proliferation and metastasis of tumors benefit from GABA synthesized by not only cancer cells but also from the tumor microenvironment. Young et al 83 reviewed the similarity of the brain and stem cell niches of peripheral organs and reported that GABAergic components were expressed in both normal and tumor conditions in the brain and peripheral organs. Neman et al 84 found that the breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABA components, including GABAAR, GABA transporter, GABA transaminase, parvalbumin, and reelin, are all highly expressed in the metastasis of breast cancer to the brain. This indicates that breast cancers may metastasize to the brain when they escape their normative genetic constraints to adapt and coinhabit the neural microenvironment. GABAergic signaling not only provides the biosynthetic energy source for cancer proliferation but also disturbs normal cell proliferation, resulting in abnormal proliferation. All these findings pave the way for the development of a potential therapeutic target that disturbs the cancer microenvironment to inhibit tumor growth and metastasis for improved prognosis.

| Cancer immunometabolism
Recent studies in the field of cancer immunometabolism have demonstrated that the production and consumption of metabolic products by different immune cells in various stages of differentiation and activation influence antitumor immune potential. 85,86 These small metabolites produced during the differentiation and activation of immune cells have better evolutionary potential as communication molecules than agents of classical signaling regulated by cytoplasmic, membrane-bound, or secreted proteins. They can use fewer cellular resources for faster synthesis and secretion. Much attention has focused on the metabolism of glucose, amino acids, and fatty acids, although little is known about the role of metabolite GABA. A recent study by Zhang et al 87 reported that GABA is synthesized and secreted by activated B cells and confirmed that it can increase the expression of IL-10 receptors, promote the differentiation and survival of antiinflammatory macrophages, and regulate the antitumor responses of CD8 + T cells through GABA A R in a mouse model of colon cancer. Previous studies demonstrated that several immune cells express GABA A R, and the activation of GABA A R through GABA binding inhibits inflammation. The activation of GABA A R on T cells restrains inflammatory T cells, namely, helper CD4 + T cells and killer CD8 + T cells, [88][89][90] while augmenting the numbers of regulatory T cells, which restricts inflammation. 12,89 Also, the activation of GABA A R on antigen-presenting cells reduces their pro-inflammatory properties. [91][92][93] Zhang et al 87 found that a GABA A R agonist named muscimol can inhibit the activation and proliferation of tumor-infiltrating CD8 + T cells, whereas the GABA A R antagonist picrotoxin can promote the cytotoxic activity of CD8 + T cells and limit tumor growth in vivo. The use of picrotoxin paves a way for targeting metabolite signaling to boost the efficacy of immune checkpoint interaction and chimeric antigen receptor T-cell (CAR-T) therapies.
A new study by Huang et al 27 more broadly reveals the molecular and functional mechanism of GABA in the inhibition of antitumor immunity. Rather than serving as metabolic fuel or building blocks, GABA derived from lung and colon cancers activates GABA B R to stabilize βcatenin induced by the ectopic expression of GAD1. Thus, it suppresses the expression of CCL4 and CCL5 to prevent the recruitment of dendritic cells, subsequently promoting tumor progression in an autocrine manner and inhibiting antitumor immune cell infiltration in a paracrine manner.
This emerging work reinforces the need to annotate metabolites within the cancer microenvironment, as it may boost the development of targeted therapy for the inhibition of tumor growth and metastasis through immunomodulation and metabolites.

RECEPTORS FOR CANCER THERAPY
With growing evidence implicating the role of GABA receptors in tumor progression and metastasis, a novel strategy for cancer treatment by manipulating GABA receptors comes in view. Hence, GABA agonists and antagonists represent direct therapeutic strategies for cancer treatment ( Table 2). The functional activity of GABA A R can be enhanced by GABA A R agonists, including benzodiazepines, barbiturates, zolpidem, and propofol, and can be attenuated by GABA A R antagonists, including bicuculline and flumazenil (which attach at the GABA A R recognition site) and picrotoxin (which attaches elsewhere on the receptor complex). 94 Like GABAAR, the activity of GABA B R is also regulated by certain drugs. For instance, it can be activated by baclofen and competitively antagonized by phaclofen. A growing body of selective GABA B R agonists and antagonists has been developed, such as the agonist CGP44532 and the antagonists CGP55845, CGP54626, and CGP35348.
Nembutal, a barbiturate, exerts agonistic effects on GABA and is a common anesthetic, hypnotic, and anticonvulsive drug. 95 Thaker et al 19 first confirmed that nembutal effectively inhibits both primary development and metastasis of colon cancer by promoting apoptosis in vivo. Further, Joseph et al 59 used baclofen as a specific GABA B R agonist to inhibit the norepinephrine-induced migration of colon carcinoma cells. Wang et al 96 demonstrated that baclofen also suppresses HCC tumor cell growth both in vitro and in vivo, and these inhibitory effects can be abrogated by pretreatment with phaclofen. Baclofen may function by suppressing cell proliferation with G0/G1 phase arrest by inhibiting cyclic adenosine monophosphate (cAMP) and downregulating the protein level and phosphorylation of p21 WAF1 . 96 In prostate cancer, although baclofen had no effect on tumor growth, GABA A R antagonists such as picrotoxin have demonstrated antitumor efficacy. 54,73 Similar anti-proliferative effects have been obtained using GABA A R antagonists such as flumazenil and bicuculline in cancers. 30,97 GABA B R antagonists, including CGP55845, CGP54626, and CGP35348, can inhibit GABA B R-induced migration. 18,74,75,79 Kanbara et al 75 confirmed that these antitumor effects may be implemented via different signaling pathways, including Ca 2+ channels, cell cycle arrest, and apoptosis in cancer cells.
Although GABA receptor agonists and antagonists have significant benefits on the behavior of tumors by suppressing the proliferation and metastasis of cancer cells, their dual effect on cancers cannot be ignored. Contrary to the inhibitory effect of baclofen (GABA B R agonist) in colon and liver cancers, baclofen can exert the opposite effect on other cancers. Baclofen significantly promoted cell invasion and migration in vitro and metastasis in vivo. 74,79 The GABA A R agonist propofol activates GABA A R to downregulate the expression of the tripartite motif (TRIM)21, consequently upregulating the expression of Src, a protein that regulates cell adhesion and extension, causing the potentiation of tumor metastasis in vivo. 98 Similarly, breast carcinoma cells also responded to propofol with increased migration which was mediated by calcium influx and actin reorganization. 99 As baclofen and propofol are both commonly used anesthetics in surgical tumor resection, their pro-metastatic effects need careful deliberation for the surgeon.  These studies provide a novel-targeted treatment of individuals using GABA receptor agonists or antagonists modulating GABA for the prevention of several cancers, as well as suggest clinical considerations for cancer metastasis. While several existing agonists and antagonists can selectively target GABA A R and GABA B R, [100][101][102] it is vital to maximize the utilization of appropriate compositions to optimize antitumor efficacy, owing to the significantly varying expressions of different receptor subtypes on cancer cells. These studies are needed to facilitate the development of various structural types of GABA agonists or antagonists for the treatment of cancers.

| CONCLUSIONS AND PERSPECTIVE
GABAergic agents significantly vary from cancer tissues to paired noncancerous tissues and exert regulatory effects on the biological characteristics of cancer cells. The distinct effects of GABA receptors on cancer progression in multiple tumor types depend on both receptor type and physiological context. In most cases, GABA regulates cancer cell proliferation through the GABA A R pathway but regulates cancer cell invasion through the GABA B R pathway. Moreover, the regulatory signaling downstream of GABA receptors includes cAMP, EGFR, AKT, MAPK/ERK, and MMP. Presumably, the disparate subunits of GABA receptors target their specific downstream signaling to modulate cancer progression. The function and mechanism of GABA A R P , a subunit of GABA, are thoroughly described in multiple cancers (including PDAC, breast cancer, ovarian cancer, and OSCC), which underscores the pivotal role of GABA A R in cancer progression, with more subunits needing similar elucidation. A normal human body can maintain a balance in the GABAergic system. However, the altered expression of GABAergic components in the peripheral organs indicated the control of the cancer microenvironment on the proliferation of normal and cancer cells. Studies by Zhang et al and Huang et al 27 add insights into how GABAergic components influence the immune microenvironment and tumor progression. This provides evidence for a novel therapeutic strategy for the treatment of cancers by modulating the GABAergic system.
Given the widespread distribution of GABAergic neurons in the nervous system, the most common side effects of drugs associated with GABA receptors include impaired CNS functions, such as sedation, ataxia, motor incoordination, anterograde amnesia, and paradoxical excitement. For instance, existing GABA A R inhibitors such as picrotoxin and bicuculline can induce severe convulsions in vivo due to their effect on GABA A R in the CNS. 103 Therefore, an important strategy to avoid the risk of severe adverse reactions involves the development of selective GABA receptor agonists and antagonists that are highly specific to the receptor subunits (e.g., GABA A R P ) and cannot penetrate the blood-brain barrier. Anesthetic drugs such as baclofen and propofol have an indispensable effect on tumor growth and metastasis, which is related to GABA receptors. These findings will attract more attention to the correlation between anesthesia and cancer metastasis, facilitating better prognosis for patients undergoing tumor resection.
In conclusion, the expression and molecular functions of GABA and its receptors in various cancers suggest that the GABAergic system is a potential target for anticancer therapy. This review provides an avenue for the development of more selective drugs that manipulate the activity of GABA receptors.