Insights into the leveraging of GABAergic signaling in cancer therapy

Tian‐Jiao Li; Jian Jiang; Ya‐Ling Tang; Xin‐Hua Liang

doi:10.1002/cam4.6102

. 2023 May 18;12(13):14498–14510. doi: 10.1002/cam4.6102

Insights into the leveraging of GABAergic signaling in cancer therapy

Tian‐Jiao Li ¹, Jian Jiang ², Ya‐Ling Tang ^3,^✉, Xin‐Hua Liang ^1,^✉

PMCID: PMC10358225 PMID: 37199392

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.

Keywords: cancer, carcinogenesis, GABA, GABA receptor, neurotransmitter

1. INTRODUCTION

Gamma‐aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system (CNS) that acts via the activation of specific GABA receptors. GABA is synthesized from glutamate, glutamine, and glucose by the glutamic acid decarboxylase enzymes GAD65 and GAD67 in the CNS. ¹ , ² GABA is activated by combining ionotropic GABA_A receptors or metabotropic GABA_B receptors ³ and controls the proliferation, differentiation, migration, and death of cells during nervous system development. ⁴ Recent studies revealed that GABA and its receptors also express and have diverse physiological functions in the development and maturation of nonneuronal peripheral tissue, ⁵ including the palate, ⁶ , ⁷ lungs, ⁸ , ⁹ digestive tract, ¹⁰ , ¹¹ pancreas, ¹² liver, ¹³ testicular cells, ¹⁴ , ¹⁵ and even stem cells. ¹⁶

Neurotransmitter systems contribute to multiple malignancies. Increasing reports demonstrated that the expression of GAD, GABA, and GABA receptors was significantly higher in cancers, including colon cancer, lung cancer, and gastric cancer than in normal tissues. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ Cancer cell proliferation and invasion are regulated by the binding of GABA to GABA_A or GABA_B receptors, thus, opening new avenues to develop pharmacological agonists and antagonists for cancer therapy. This review describes the potential mechanisms of GABAergic signaling in cancer development and progression and the possible treatment of cancer using GABA receptor‐associated drugs.

2. 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 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.

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, mitogen‐activated protein kinase/extracellular signal‐related kinase; MMP, matrix metalloproteinase; TCA, tricarboxylic acid.

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_AR) 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_AR channels closely depend on their subunit composition. The most abundant GABA_AR subtype consists of two α, two β, and one γ subunits. ³⁷ GABA_AR 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_AR possesses several allosteric binding sites for anxiolytic, hypnotic, anesthetic, and anticonvulsant drugs. ³⁸ For instance, bicuculline and picrotoxin are antagonists of GABA_AR, whereas propofol and benzodiazepines are its agonists. ³⁹ , ⁴⁰ , ⁴¹ GABA_B receptors (GABA_BR) are members of the family of heterodimeric G‐protein‐coupled receptors, which are composed of two main GABA_BR subunits termed GABA_B receptor 1 (GABA_BR₁) subunit and GABA_BR₂ 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_BR can be activated by GABA to regulate Ca²⁺ channels and K⁺ channels. ⁴³ , ⁴⁴ GABA activates serious proteins connecting with the C‐termini of GABA_BR by binding with the extracellular domain of GABA_BR₁, whereas the extracellular domain of GABA_BR₂ has no ligand‐binding activity. Some allosteric modulators, such as CGP7930, can bind the transmembrane domain of GABA_BR₂ to modulate the binding affinity of the ligand with GABA_BR₁, as well as the efficacy of signal transduction after binding. ⁴⁵ However, the mechanisms governing downstream signaling remain unclear.

GABA_A receptor and GABA_B receptor molecular and functional structure. (A) GABA_AR is a pentameric ligand‐gated ion chloride channels consisting of five transmembrane subunits. The most abundant GABA_AR subtype consists of 2α, 2β, and 1γ subunits. GABA_AR is activated by binding with GABA to open Cl⁻ channel. (B) GABA_BR is a heterodimeric G‐protein‐coupled receptor composed of the GABA_BR₁ subunit and GABA_BR₂ subunit. The subunits interact with each other via intracellular coiled‐coil domains near the C terminus. The intracellular loops of GABA_BR₂ are coupled to Gi/o‐type G‐proteins. The extracellular domain of GABA_BR₁ can bind GABA, whereas the extracellular domain of GABA_BR₂ has no ligand‐binding activity. GABA_BR is activated by binding with GABA to regulate K⁺ channels and Ca²⁺ channels. GABA_AR, GABA_A receptor; GABA_BR, GABA_B receptor; GABA_BR₁, GABA_B receptor 1; GABA_BR₂, GABA_B receptor 2.

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.

3. GABAergic SIGNALING IN CANCER

3.1. 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 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_AR and cellular invasion through GABA_BR. 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.

TABLE 1.

The expression, effect, and pathways of GABA and GABA receptors in different cancers.

Region	Cancer	Expression	Cancer development	Mechanisms	Studies
Brain	Glioblastoma	GABA_AR₁ ↑	Negative	GABA_AR, miR‐155	104, 105
Head and neck	Oral cancer	GAD1↑, GABA_AR_P↑	Positive	GAD1, GABA_AR_P	56, 81
Head and neck	Nasopharyngeal carcinoma	GAD1↑	Positive	GAD1	³¹
Lung	NSCLC	GABA↓, GABA_AR_A3↑, GABA_AR_E↑, GABA_BR₂↑	Negative	GABA_BR, cAMP	57, 106
Lung	PAC	GABA↓	Negative	GABA_BR, cAMP, Erk1/2	⁵⁸
Breast	Breast cancer	GABA↓	Negative	GABA_AR	66, 99
Stomach	Gastric cancer	GABA↑, GAD65(+), GABA_AR (+), GABA_BR (−)	Positive	GABA_AR, MAPK/ERK	²³
Liver	Hepatocellular carcinoma (HCC)	GABA_AR_β3↓	Negative	GABA_AR_β3, GABA_BR cAMP, ERK1/2	62, 63, 96
	Hepatocellular carcinoma (HCC)	GABA_AR_Q↑, GABA_AR_A3↑	Positive	GABA_AR	17, 61
	Cholangiocarcinoma	GABA_AR_β3 (+), GABA_BR₁(+), GABA_CR (+)	Negative	GABAR, cAMP, MAPK/ERK	⁶⁰
Colon	Colon cancer	GABAR (+)	Negative	GABAR, cAMP, MMP	19, 59
Pancreas	PDAC	GABA↓	Negative	GABA_BR, cAMP, ERK1/2	⁶⁴
Pancreas	PDAC	GABA_AR_P↑	Positive	GABA_AR_P, MAPK/ERK	³⁰
Prostate	Prostate cancer	GABA↑, GAD67↑, GABA_AR↑	Positive	GABA_AR and GABA_BR, MMP	18, 22
Ovarian	Ovarian cancer	GABA↑	Positive	GABA_AR_P	55, 107
Thyroid	Thyroid tumors	GABA_AR_B2↑, GABA_AR_A2 (+), GABA_BR₂↑	Positive	GABA_AR_β2, GABA_AR_α2, GABA_BR₂	¹⁰⁸

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Abbreviations: GAD, glutamic acid decarboxylase enzymes; GABAR, GABA receptor; GABA_AR₁, GABA_A receptor 1; GABA_AR_A2, GABA_A receptor subunit α2; GABA_AR_A3, GABA_A receptor subunit α3; GABA_AR_E, GABA_A receptor subunit ε; GABA_BR₂, GABA_B receptor subunit 2; GABA_AR_Q, GABA_A receptor subunit θ; GABA_AR_P, GABA_A receptor subunit π; GABA_AR_β2, GABA_A receptor subunit β2; GABA_AR_β3, GABA_A receptor subunit β3.

3.1.1. 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 , ⁶² , 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_AR θ subunit (GABA_AR_Q), while Yan et al ⁶¹ found that this effect occurs through the GABA_AR α3 subunit (GABA_AR_A3). However, other subunits of GABA receptors may play an opposite role. Minuk et al ⁶² reported that the expression of hepatic GABA_AR β3 subunit (GABA_AR_B3) was downregulated in human HCC, and its restoration can attenuate tumor growth in nude mice. In PDAC, Takehara et al ³⁰ observed that GABA promoted the proliferation of PDAC cells through the GABA_AR π subunit (GABA_AR_P), whereas Schuller et al ⁶⁴ demonstrated that GABA inhibited PDAC cell proliferation and migration by inhibiting the isoproterenol‐stimulated pathway, which may be suppressed in human PDAC tissue. In breast cancer, GABA promotes the proliferation and invasion of breast cancer cells through GABA_BR_1e, GABA_AR_A3, ⁶⁸ and GABA_AR_P. ⁶⁷ However, Drell et al ⁶⁶ reported that GABA inhibited the norepinephrine‐induced migration of breast cancer cells, which may be mediated by GABA_BR, as confirmed by the use of a specific GABA_BR agonist, baclofen. The dichotomous role of GABA on cancers may be attributed to the diverse subunits of GABA receptors.

3.1.2. The effect of GABA_A receptors on cancers

Several studies have reported that GABA can promote cell proliferation through the GABA_AR in cancers such as HCC, ¹⁷ , ⁶¹ prostate cancer, ²² , ⁵⁴ gastric cancer, ²³ breast cancer, ⁶⁷ , ⁶⁸ PDAC, ³⁰ and OSCC, ⁵⁶ and inhibit cell proliferation through the GABA_AR in cancers such as HCC ⁶² and cholangiocarcinoma. ⁶⁰ The GABA_AR_Q and GABA_AR_A3 subunits of GABA_AR, which mediate inhibitory synaptic transmission in the CNS, were overexpressed in HCC tissues compared with adjacent nontumor liver tissues, and the knockdown of GABA_AR_Q and GABA_AR_A3 expression in malignant hepatocytes resulted in attenuated tumor growth both in vitro and in vivo. ¹⁷ , ⁶¹ In contrast, GABA_AR_B3 exerts an opposite function. ⁶² The overexpression of GABA_AR_A3 also promoted the migration, invasion, and metastasis of breast cancer cells. ⁶⁸ GABA_AR_P, a subunit of GABA_AR, 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_AR_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_AR appeared to play a vital role. GABA_AR_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_AR_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_BR 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_BR_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_BR₂ with a low expression of GABA_AR_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_AR and GABA_BR in cancers have revealed the potential downstream pathways of GABA receptors.

3.2. 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).

3.2.1. 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_BR 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_BR contributed to the development and maintenance of CIBP, and the restoration of depleted GABA_BR 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.

3.2.2. 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_AR 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_AR_A1 might participate in this tumor‐promoting action by activating EGFR and the downstream signaling molecule Src. GABA_BR can also transactivate EGFR through a ligand‐dependent mechanism, thus promoting the migration and invasion of prostate cancer cells. ⁷⁴ Furthermore, the GABA_BR agonist baclofen selectively causes multisite phosphorylation of tyrosine residues associated with EGFR ubiquitination. ⁷⁴ Further the research group ⁶⁵ describes that GABA_BR_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.

EGFR‐mediated carcinogenesis may function by continuously phosphorylating downstream signaling effectors, including phosphatidylinositol‐3‐kinase (PI3K), protein‐serine–threonine kinase (AKT), or mitogen‐activated protein kinase (MAPK) pathways.

3.2.3. 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 epithelial‐mesenchymal 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_AR has been shown to regulate EGFR activation in prostate cancer, this condition was not observed in breast cancer cells. The overexpression of GAB_AR_A3 promotes the migration and metastasis of breast cancer through AKT signaling. ⁶⁸ GAB_AR_A3 may mediate signaling molecules upstream of the AKT pathway, like PI3K, rather than EGFR. Conversely, GABA_BR can mediate the EGFR‐AKT signaling pathway. Moreover, in breast cancer, GABA_BR_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

3.2.4. 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 Ca²⁺, induced by GABA to influence neurogenesis and synaptogenesis, activates the small guanine nucleotide‐binding protein Ras and stimulates the MAPK cascade. ⁷⁸ GABA_AR, particularly GABA_AR_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_AR_P by activating the MAPK/ERK cascade by increasing intracellular Ca²⁺ levels. ³⁰ , ⁵⁵ , ⁶⁷ Similarly, GABA_AR_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_AR, followed by the activation of MAPK/ERK and an increase in cyclin D1. ²³ Besides GABA_AR, GABA_BR 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/Ca²⁺‐dependent pathways followed by the downregulation of ERK‐1/2 phosphorylation and cAMP. ⁶⁰

3.2.5. 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_BR, 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_BR downregulates the phosphorylation of ERK1/2 via the cAMP/PKA‐dependent pathway ⁶⁰ and consequently promotes the production of MMPs. ⁷⁹ GABA_BR 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_BR 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.

3.3. 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.

3.4. 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 anti‐inflammatory macrophages, and regulate the antitumor responses of CD8⁺ T cells through GABA_AR in a mouse model of colon cancer. Previous studies demonstrated that several immune cells express GABA_AR, and the activation of GABA_AR through GABA binding inhibits inflammation. The activation of GABA_AR 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_AR on antigen‐presenting cells reduces their pro‐inflammatory properties. ⁹¹ , ⁹² , ⁹³ Zhang et al ⁸⁷ found that a GABA_AR agonist named muscimol can inhibit the activation and proliferation of tumor‐infiltrating CD8⁺ T cells, whereas the GABA_AR 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_BR to stabilize β‐catenin 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.

4. TARGETING GABA 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_AR can be enhanced by GABA_AR agonists, including benzodiazepines, barbiturates, zolpidem, and propofol, and can be attenuated by GABA_AR antagonists, including bicuculline and flumazenil (which attach at the GABA_AR recognition site) and picrotoxin (which attaches elsewhere on the receptor complex). ⁹⁴ Like GABAAR, the activity of GABA_BR 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_BR agonists and antagonists has been developed, such as the agonist CGP44532 and the antagonists CGP55845, CGP54626, and CGP35348.

TABLE 2.

The potential GABA agonists and antagonists as cancer therapy drugs.

Classification	Name	Target	Cancer	Effect	Researches
Agonists	Benzodiazepines	GABA_AR	Medulloblastoma	Inhibitory	¹⁰⁹
	Nembutal	GABA_AR	Colon cancer	Inhibitory	¹⁹
	Propofol	GABA_AR	Lung cancer, breast cancer	Promotive	98, 99
	Baclofen	GABA_BR	Colon cancer, Hepatocellular carcinoma	Inhibitory	59, 96
	Baclofen	GABA_BR	Breast cancer, prostate cancer	Promotive	⁷⁴
	CGP7930	GABA_BR	Prostate cancer	Promotive	⁷⁴
Antagonists	Bicuculline	GABA_AR	Pancreatic Cancer	Inhibitory	³⁰
	Flumazenil	GABA_AR	Metastatic neuroendocrine cancers	Inhibitory	⁹⁷
	Picrotoxin	GABA_AR	Prostate cancer	Inhibitory	⁵⁴
	CGP55845	GABA_BR	Breast cancer	Inhibitory	⁷⁹
	CGP54626	GABA_BR	Prostate cancer, high‐grade chondrosarcoma	Inhibitory	74, 75
	CGP35348	GABA_BR	Prostate cancer	Inhibitory	¹⁸

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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_BR 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_AR antagonists such as picrotoxin have demonstrated antitumor efficacy. ⁵⁴ , ⁷³ Similar anti‐proliferative effects have been obtained using GABA_AR antagonists such as flumazenil and bicuculline in cancers. ³⁰ , ⁹⁷ GABA_BR antagonists, including CGP55845, CGP54626, and CGP35348, can inhibit GABA_BR‐induced migration. ¹⁸ , ⁷⁴ , ⁷⁵ , ⁷⁹ Kanbara et al ⁷⁵ confirmed that these antitumor effects may be implemented via different signaling pathways, including Ca²⁺ 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_BR 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_AR agonist propofol activates GABA_AR 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_AR and GABA_BR, 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.

5. 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_AR pathway but regulates cancer cell invasion through the GABA_BR 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_AR_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_AR 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_AR inhibitors such as picrotoxin and bicuculline can induce severe convulsions in vivo due to their effect on GABA_AR 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_AR_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.

AUTHOR CONTRIBUTIONS

Tianjiao Li: Conceptualization (lead); data curation (equal); methodology (equal); project administration (equal); resources (equal); visualization (equal); writing – original draft (lead); writing – review and editing (lead). Jian Jiang: Conceptualization (equal); investigation (equal); methodology (equal); writing – original draft (supporting); writing – review and editing (supporting). Yaling Tang: Conceptualization (lead); formal analysis (equal); funding acquisition (lead); writing – review and editing (lead). Xinhua Liang: Conceptualization (lead); funding acquisition (lead); investigation (lead); resources (equal); writing – review and editing (lead).

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to declare.

ACKNOWLEDGMENTS

This work was supported by National Natural Science Foundation of China grants (Nos. 82073000, 82173326), National Science Foundation of Sichuan Province (Nos. 2022YFS0289 and 2022NSFSC0687), and Exploration and Research Projects of West China College of Stomatology, Sichuan University (LCYJ2020‐YJ‐1).

Li T‐J, Jiang J, Tang Y‐L, Liang X‐H. Insights into the leveraging of GABAergic signaling in cancer therapy. Cancer Med. 2023;12:14498‐14510. doi: 10.1002/cam4.6102

Tian‐Jiao Li and Jian Jiang contributed equally to this work.

Contributor Information

Ya‐Ling Tang, Email: tangyaling@scu.edu.cn.

Xin‐Hua Liang, Email: lxh88866@scu.edu.cn.

DATA AVAILABILITY STATEMENT

Data availability is not applicable to this article as no new data were created or analyzed in this study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data availability is not applicable to this article as no new data were created or analyzed in this study.

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PERMALINK

Insights into the leveraging of GABAergic signaling in cancer therapy

Tian‐Jiao Li

Jian Jiang

Ya‐Ling Tang

Xin‐Hua Liang

Abstract

1. INTRODUCTION

2. THE GABAergic SYSTEM

FIGURE 1.

FIGURE 2.

3. GABAergic SIGNALING IN CANCER

3.1. The effects of GABA and its receptors in different cancers

TABLE 1.

3.1.1. The effects of GABA on cancers

3.1.2. The effect of GABAA receptors on cancers

3.1.3. The effect of GABAB receptors on cancers

3.2. The mechanisms of GABAergic signaling in cancer progression and metastasis

3.2.1. cAMP pathway

3.2.2. EGFR pathway

3.2.3. AKT pathway

3.2.4. MAPK/ERK pathway

3.2.5. MMP pathway

3.3. Cancer microenvironment

3.4. Cancer immunometabolism

4. TARGETING GABA RECEPTORS FOR CANCER THERAPY

TABLE 2.

5. CONCLUSIONS AND PERSPECTIVE

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

ACKNOWLEDGMENTS

Contributor Information

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

3.1.2. The effect of GABA_A receptors on cancers

3.1.3. The effect of GABA_B receptors on cancers