Role of nitric oxide, prostaglandins, thromboxanes and endothelins in lung cancer: An overview

Abstract

Lung cancer is the most frequent cause of cancer-related mortality worldwide. Nitric oxide (NO), prostaglandins (PGs), thromboxanes (TXs), and endothelins (ETs) participate in numerous physiological processes. These agents play an important role in lung carcinogenesis by regulating cancer cell proliferation, apoptosis, invasion, and angiogenesis. NO is a gaseous free radical with tumoricidal and tumorigenic activities in lung cancer. Arachidonic acid-derived PGs, including PGD₂, PGE₂, 8-iso-PGF_2α, and PGI₂, are related to the development of lung cancer. PGD₂ and PGI₂ act as tumor suppressors, while PGE₂ and 8-iso-PGF_2α promote tumor progression. TXA₂ catalyzed by cyclooxygenase induces proliferation as well as angiogenesis. Elevated levels of TXB₂, an inactive metabolite of TXA₂, are positively correlated with lung carcinoma stages. ET-1 and ET-2 are 21 amino acid polypeptides; their silencing hinders lung cancer cell proliferation and invasion. ET-2 depletion also triggers apoptotic death. This chapter review aims to provide a comprehensive overview of the role of NO, PGs, TXs, and ETs in lung cancer.

Key Words: Endothelins; Lung cancer; Nitric oxide; Prostaglandins; Thromboxanes

Core Tip: Lung cancer remains the leading cause of cancer-related deaths globally. Nitric oxide (NO), prostaglandins (PGs), thromboxanes (TXs), and endothelins (ETs) significantly influence lung carcinogenesis by modulating cancer cell proliferation, apoptosis, invasion, and angiogenesis. This study highlights the dual roles of NO, the opposing effects of arachidonic acid-derived PGs, the involvement of TXA₂ and its metabolite TXB₂, and the critical functions of ETs in lung cancer progression. The findings emphasize the complex interplay of these agents in tumor biology, offering insights for potential therapeutic targets.

INTRODUCTION

Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related mortality in the world[1]. In 2024, it was estimated that there were 2001140 new cases of lung cancer and 611720 deaths in the United States[2]. The incidence rate was 27% higher in men than women between 2015 and 2019[3]. Lung cancer is a complex and heterogeneous disease due to genetic diversity in histological subtypes with clinical relevance[4]. The primary etiologic factor is tobacco smoking for lung cancer. Other etiologic factors are environmental and occupational exposures to agents, such as second-hand smoke, air pollution, radiation, asbestos, nickel, arsenic, and silica[5].

Lung cancer is classified into two main types: Small cell lung cancer (SCLC) and non- SCLC (NSCLC). SCLC arises from pulmonary neuroendocrine cells, representing 13% of all lung cancer cases[6,7]. NSCLC originates from lung epithelial cells, accounting for 87% of the cases[8,9]. NSCLC comprises the subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma[10].

SEARCH STRATEGY

This review aims to provide a comprehensive overview of the roles of endogenous modulators-nitric oxide (NO), prostaglandins (PGs), thromboxanes (TXs), and endothelins (ETs)-in the molecular mechanisms underlying lung cancer. A search strategy was performed in various electronic databases, including PubMed, Scopus, Web of Science, EBSCO, and TR Dizin. The keywords included “lung cancer,” “nitric oxide,” “prostaglandin D2,” “prostaglandin I2,” “prostaglandin E2,” “8-iso-prostaglandin-F2a,” “thromboxane A2,” “thromboxane B2,” “endothelin-1,” and “endothelin-2.”

BIOLOGY OF THE ENDOGENOUS MODULATORS

This section describes the biosynthesis, receptors, signaling pathways, and biological effects of NO, PGs (PGD₂, PGI₂, PGE₂, and 8-iso-PGF_2α), TXs (TXA₂ and TXB₂), and ETs (ET-1 and ET-2), with associated figures contributing to the understanding. The multifunctional endogenous modulators play essential roles in physiological processes and are used as biomarkers for various pathological conditions.

NO

NO is an endogenously synthesized free radical and short-lived diatomic gas[11]. It is produced in endothelial cells, airway epithelial cells, kuffer cells, macrophages, and natural killer cells by NO synthase (NOS) isoforms, which convert L-arginine to L-citrulline[12] (Figure 1). NOS isoforms are categorized into two classes: Calcium/calmodulin-dependent and -independent[13]. Calcium/calmodulin-dependent neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3) are constitutively expressed by neurons and endothelial cells, respectively[14]. In a calcium/calmodulin-independent manner, inducible NOS (iNOS or NOS2) expression is triggered by proinflammatory molecules[15]. NOS1 and NOS3 generate NO at nanomolar levels, while NOS2 at micromolar concentrations. NO regulates vascular function, metabolism, neurotransmission, and macrophage-mediated cytotoxicity[16,17].

Figure 1 The synthesis of nitric oxide.

PGs

PGs are lipid autacoids that have hormone-like activities[18]. Cyclooxygenase (COX) has COX-1 and COX-2 isoforms, which catalyze the conversion of the cell membrane lipid derivative arachidonic acid into PGH₂[19]. PGDS, PGIS, and PGES convert PGH₂ to PGD₂, PGI₂, and PGE₂, respectively (Figure 2). However, 8-iso-PGF_2α is the product of a non-enzymatic peroxidation of arachidonic acid[20]. PGD₂, PGI₂, and PGE₂ exhibit their activities via D1-2, IP, and EP1-4 receptors, respectively. 8-iso-PGF_2α binds to the receptor of TXA₂[21]. PGs play a role in various physiological and pathological processes, including vascular reactivity, platelet aggregation, and inflammation[22,23]. Moreover, 8-iso-PGF_2α is a potential biomarker for oxidative stress and lipid peroxidation[24,25].

Figure 2 The synthesis of prostaglandins.

TXs

TXA₂ is produced in endothelial cells, platelets, macrophages, and neutrophils through COXs and TXA₂ synthase (TXA₂S)[26]. TXA₂ interacts with the TXA₂-prostanoid receptor (TP) on the cell surface[27]. TP isoforms TPα and TPβ couple to G proteins[28]. TPα isoform is expressed in more tissues than TPβ[29]. TXA₂ is spontaneously hydrolyzed non-enzymatically to the stable TXB₂ metabolite[30] (Figure 3). TXA₂ is involved in promoting vasoconstriction and platelet aggregation[31]. TXB₂ leads to bronchoconstriction and inflammation[32,33].

Figure 3 The synthesis of thromboxanes.

ETs

ET peptides, ET-1 and ET-2, are encoded by two distinct genes[34]. ETs are 21-amino acid polypeptides that result from the cleavage of big ETs through ET-converting enzymes (ECEs)[35] (Figure 4). ET-1 is synthesized in various tissues, such as endothelial cells, smooth muscle cells, and neurons, whereas ET-2 is abundant in intestinal epithelial cells and ovaries[36]. ETs mediate biological processes by activating ET_A and ET_B receptors[37]. ET-1 and ET-2 act as constrictor agents in vascular and airway smooth muscle cells[38,39].

Figure 4 The synthesis of endothelins.

THE ENDOGENOUS MODULATORS in MOLECULAR MECHANISMS of LUNG CANCER

This section provides a comprehensive overview of the roles of endogenous modulators in the molecular mechanisms of lung cancer. The following studies present the effects and levels of NO, PGs, TXs, and ETs on lung carcinogenesis, with associated tables contributing to the understanding.

The effects and levels of NO on lung cancer

Table 1 summarizes 16 studies on the effects of NO in lung cancer models, including H460, LLC-1, H292, H23, A549, H1299, CL3, and H3255 cell lines, as well as patients. Results indicated that NO contributes to lung cancer development and progression via migratory, tumorigenic, anti-apoptotic, and metastatic effects. NO may promote growth and stemness maintenance and cause resistance to drugs and radiation. Moreover, the factor has apoptotic properties on lung cancer.

Table 1 Effects of nitric oxide on lung cancer models.

Factor	Models	Effects	Ref.
Nitric oxide	H460 cell line	Migratory	[40]
	LLC-1 cell line	Apoptotic	[41]
	Lung cancer patient	Tumorigenic	[42]
	Lung cancer tissue	Anti-apoptotic	[43]
	NCI-H292 cell line	Anti-apoptotic	[44]
	H23 cell line	Migratory	[45]
	Lung cancer patient	Tumorigenic	[46]
	H292 and H460 cell lines	Tumorigenic	[47]
	H23, H292, and H460 cell lines	Migratory	[48]
	Anoikis-resistant H460 cell line	Metastatic	[49]
	A549, H1299, and CL3 cell lines	Apoptotic	[50]
	Cisplatin-resistant A549 cells	Drug resistance	[51]
	KRAS mutation-positive mice	Growth	[52]
	A549 and H3255 cell lines	Radiation resistance	[53]
	-	Stemness maintenance	[54]
	LUAD patient	Tumorigenic	[55]

LLC-1: Lewis lung carcinoma; LUAD: Lung adenocarcinoma.

Sanuphan et al[40] investigated the prolonged effects of NO treatment on H460 Large cell lung cancer cell motility. Results from the study suggested that NO exposure augmented tumor cell migration and invasion, which was related to the upregulation of caveolin-1 expression, possibly through the FAK-Akt cascade. Moreover, NO caused an increase in the filopodia formation and cell division cycle 42 protein levels.

Confino et al[41] examined the roles of gaseous NO on the Lewis lung carcinoma (LLC-1) cells. NO led to a decrease in cell viability in a time-dependent manner. However, gaseous NO developed resistance to the second LLC-1 vaccination in vivo. These results indicated that NO may inhibit local and distant metastases due to its non-carcinogenic properties.

Koçer et al[42] reported a positive correlation between the b allele and b/b genotype frequency of the intron four variable number of tandem repeat (VNTR) polymorphism in the eNOS gene and epidermoid lung cancer. In this regard, the eNOS gene-related intron 4 VNTR may be counted among genetic risk factors for lung cancer.

Chen et al[43] investigated the tobacco carcinogen NNK exposure on tissue samples from lung cancer cases. In NNK-treated cells, iNOS levels enhanced while decreasing caspase-3 levels. Therefore, iNOS may have anti-apoptotic activities.

Wongvaranon et al[44] showed that long-term NO exposure led to resistance against chemotherapeutic drugs, such as doxorubicin, cisplatin (CDDP), and etoposide, via caveolin-1, B-cell lymphoma-2, and Akt.

Chanvorachote et al[45] investigated the role of extended NO treatment on lung cancer H23 cells. NO exposure may elicit cell motility by inducing lamellipodia formation. NO exhibited a migratory effect and resistance to anoikis through epithelial-mesenchymal transition (EMT) and caveolin-1. Moreover, prolonged exposure to nontoxic concentrations of NO promoted EMT in H292 and H460 cells.

Peddireddy et al[46] detected a significant correlation between the a/a genotype frequency of the eNOS gene polymorphism and NSCLC in the South Indian population.

Yongsanguanchai et al[47] reported that NO promoted the expression of cancer stem cell markers and triggered migration and colony formation in H292 and H460 cells. Additionally, it enhanced resistance to anoikis.

Saisongkorh et al[48] found that the nontoxic NO doses increased the expression of integrin αv and β1 in H23, H292, and H460 cells. The migratory effect may be related to the protein kinase G/Akt signaling pathway.

Powan and Chanvorachote[49] demonstrated that NO led to E-cadherin-mediated cell aggregation in anoikis-resistant H460 cells.

Chao et al[50] examined survivin expression in NO-treated A549, H1299, and CL3 cells. Exogenous NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP), and endogenous iNOS caused cell death by inhibiting survivin expression. The apoptotic effects of SNP and iNOS were concerned with the p38 MAPK pathway. SNAP inhibited cell growth while increasing G₂/M phase fractions. SNAP led to a decrease in cyclin B1 levels; however, it did not significantly change cdc2 levels.

Li et al[51] found that iNOS enhanced CDDP resistance in A549 cells through the canonical Wnt/β-catenin signaling pathway.

Pershing et al[52] investigated the role of L-NAME, a NOS inhibitor, in mice with KRAS mutation-positive NSCLC. The findings showed that L-NAME reduced cell growth in vivo.

Saleem et al[53] reported that decreased NO levels augmented radiosensitivity in the hypoxic A549 and H3255 cells. Additionally, the reduction caused the downregulation of epidermal growth factor receptor (EGFR) and hypoxia-inducible factor-1α expressions, especially in H3255 cells.

Zhang et al[54] showed that NO-induced S-nitrosylation and deubiquitination of the Notch1 protein maintained cancer stem cell stemness.

Fujimoto et al[55] demonstrated a significant relationship between NOS activity and p53 mutation in patients with early-stage lung adenocarcinoma (LUAD).

Table 2 summarizes nine studies on NO levels in lung cancer models. NO levels may be either low or high in patients and tissues with lung cancer.

Table 2 Levels of nitric oxide on lung cancer models.

Factor	Models	Levels	Ref.
Nitric oxide	Lung cancer patient	High	[56]
	NSCLC patient	High	[57]
	Lung cancer patient	High	[58]
	Lung cancer patient	High	[59]
	Lung cancer patient	High	[60]
	Lung cancer patient	High	[61]
	Lung cancer tissue	High	[62]
	Lung cancer patient	High	[63]
	NSCLC tissue	Low	[64]
	Squamous cell carcinoma tissue	High

NSCLC: Non-small cell lung cancer.

Kaynar et al[56] detected higher NO levels in the patients with SCLC and NSCLC than in the healthy subjects.

Muto et al[57] examined serum NO levels in bevacizumab plus chemotherapy-treated NSCLC patients. Results showed that NO concentration reduced after the second course of bevacizumab administration.

Yagcı et al[58] conducted a study on patients with lung cancer and found an enhancement in serum iNOS levels. According to the finding, the iNOS protein may be a biomarker candidate for lung cancer.

Gào et al[59] studied the impact of NO metabolites, nitrite and nitrate, on lung tumorigenesis. Urine samples from lung cancer patients revealed elevated levels of nitrite/nitrate.

Masri et al[60] detected higher levels of exhaled NO and nitrite in the lung cancer group than in the control group.

Liu et al[61] measured fractional exhaled NO levels using a NO analyzer in patients with various subtypes of lung cancer. The findings demonstrated that patients with SCLC and squamous cell carcinoma especially had higher levels of exhaled NO.

Speranza et al[62] indicated that the levels of iNOS mRNA and protein in lung cancer tissue were enhanced compared to normal lung tissue. The upregulation of iNOS may be associated with the development of lung cancer.

Sim et al[63] examined iNOS expression between pre-chemotherapy and post-chemotherapy groups with NSCLC. Results showed that iNOS levels decreased post-chemotherapy.

Ambs et al[64] suggested that Ca²⁺-dependent NOS isoforms, NOS1 and NOS3, diminished in tissue with NSCLC compared to healthy tissue. Ca²⁺-independent NOS2 expression was low in tumor and healthy tissues but significantly enhanced in squamous cell carcinomas.

The effects and levels of PGs on lung cancer

Table 3 summarizes 20 studies on the effects of PGs in lung cancer models, including A549, PC-9, GLC82, and NCI-H157 cell lines, as well as patients and mice. In this regard, PGD₂ and PGI₂ exhibit anti-cancer effects, while PGE₂ displays pro-tumor effects.

Table 3 Effects of prostaglandins on lung cancer models.

Factor	Models	Effects	Ref.
Prostaglandin D2	A549 cell line	Apoptosis	[65]
Prostaglandin I2	A549 cell line	Anti-growth	[66]
	LLC	Anti-metastatic	[67]
	LLC	Anti-metastatic	[68]
	Transgenic mice	Chemopreventive	[69]
Prostaglandin E2	NSCLC	Growth	[70]
	A549 and PC-9 cell lines	Pro-tumorigenic	[71]
	A549 and GLC82 cell lines	Proliferative	[72]
	NSCLC cell line	Apoptosis resistance	[73]
	A549 cell line	Anti-apoptotic	[74]
	A549 cell line and lung cancer mice	Multidrug resistance	[75]
	Lung cancer patients	Tumorigenic	[76]
	A549 cell line	Migratory	[77]
	NSCLC cell line	Invasive	[78]
	A549 cell line	Tumorigenic	[79]
	NSCLC cell line	Proliferative	[80]
	NSCLC cells	Metastatic	[81]
	NCI-H157 cell line	Angiogenic	[82]
	NSCLC patients	Immunosuppressive	[83]
	A549 cell line	Migratory	[84]

NSCLC: Non-small cell lung cancer; LLC-1: Lewis lung carcinoma.

Wang and Mak[65] demonstrated that PGD₂ promoted cell death in A549 cells via the intrinsic apoptotic pathway.

Fukumoto et al[66] showed that PGI₂ induced negative growth control of A549 by stimulating PPARδ.

Cuneo et al[67] investigated the effect of PGI₂ on LLC metastasis. PGI₂ blunted metastasis formation and LLC adherence to endothelial cells.

Karmali et al[68] examined the impact of nafazatrom, a stimulator of PGI₂ release, on LLC. Treatment with nafazatrom diminished lung weight. Moreover, the administration enhanced survival time in mice.

Keith et al[69] reported that the PGI₂ synthase overexpression reduced lung tumor incidence and multiplicity in transgenic mice.

Zhong et al[70] showed that PGE₂ led to upregulating the α7 nAChR gene in NSCLC via the EP4/JNK/PI3K/PKA/c-Jun pathway. PGE₂ led to NSCLC cell growth by increasing α7 nAChR expression.

Filippelli et al[71] reported that PGE₂ may exhibit pro-tumorigenic effects via the EP1-ERK5 signaling pathway.

Bazzani et al[72] presented that PGE₂ caused A549 and GLC82 cell proliferation by promoting the nuclear translocation of EGFR.

Krysan et al[73] demonstrated that PGE₂ induced apoptosis resistance through c-myc-mediated upregulation of miR-17-92, which blunted PTEN expression.

Li et al[74] investigated the roles of EP3, a PGE₂ receptor, on NSCLC progression. In A549 cells, EP3/TGFβ/Smad signaling inhibition triggered apoptosis and reduced viability, migration, and invasion.

Maeng et al[75] found that COX-2 upregulation enhanced the expression of MRP4 in A549 cells and a lung cancer mouse models via the mPGES-1/PGE₂ cascade.

Liang et al[76] assessed the roles of SNPs in COX/PGE₂ pathway-related genes in lung cancer patients. PTGS2-rs4648298, PTGS2-rs2745557, PTGER2-rs2075797, and PTGIS-rs6125671 were related to an increased risk of lung cancer.

Kim et al[77] reported that the PGE₂/EP4/β-arrestin1/c-SRC signaling pathway mediated the migration of A549 cells.

Dohadwala et al[78] displayed that PGE₂ promoted the expression of CD44 and MMP-2, which caused invasion in NSCLC cells.

Hanaka et al[79] revealed that mPGES-1 knockdown inhibited the clonogenicity and tumorigenicity of A549 cells.

Krysan et al[80] investigated the impacts of EGFR inhibitors on PGE₂-mediated NSCLC cell proliferation. The findings showed that PGE₂ stimulated the proliferation of NSCLC cells in an EGFR-independent manner. The proliferative effect was related to the MAPK-Erk signal transduction.

Wang et al[81] demonstrated that PGE₂ had a metastatic effect on NSCLC cells through USP9X/PGES.

Casibang et al[82] found that PGE₂ enhanced the mRNA expression of vascular endothelial growth factor (VEGF) mRNA in NCI-H157 by activating adenylyl cyclase. According to the results, PGE₂ may promote angiogenesis.

Baratelli et al[83] reported that COX-2/PGE₂ signaling increased the immunosuppressive activity of CD4⁺CD25^bright regulatory T cells (Treg) mediated by TGF-β in NSCLC patients.

Bai et al[84] revealed that PGE₂ and its EP1 receptor targeted the downstream signaling of NF-κB. The prostanoid increased β1-integrin expression, contributing to the migration of A549 cells.

Table 4 summarizes 16 studies on PG levels in lung cancer models. PGD₂ and PGI₂ levels were generally decreased, while PGE2 and 8-iso-PGF_2α levels were elevated in lung cancer.

Table 4 Levels of prostaglandins on lung cancer models.

Factor	Models	Levels	Ref.
Prostaglandin D2	Lung cancer tissue	Low	[85]
	NSCLC	Low	[86]
Prostaglandin I2	Lung cancer patient	Low	[87]
	neoplastic cell	Low	[88]
	Lung cancer patient	High	[89]
	Lung tumor tissue	Low	[90]
Prostaglandin E2	lung cancer tissue	High	[91]
	NSCLC cell line	High	[92]
	Lung cancer tissue	High	[85]
	Lung cancer patient	high	[93]
	NSCLC patient	High	[94]
8-Iso-prostaglandin F2α	Lung cancer patient	High	[95]
	Lung cancer patient	High	[96]
	NSCLC patient	High	[97]
	Lung cancer patient	High	[98]
	NSCLC patient	High	[99]

NSCLC: Non-small cell lung cancer.

McLemore et al[85] detected lower PGD₂ levels in lung cancer tissue than in normal lung tissue.

He et al[86] reported that PGD₂ synthase, responsible for PGD₂ production, was downregulated in NSCLC.

Dumanskiy et al[87] measured PGI₂ at low concentrations in patients with lung cancer.

Dwyer-Nield et al[88] showed that PGI₂ expression was lower in murine neoplastic cells than in non-neoplastic cells.

Xin et al[89] presented that serum levels of PGI₂ were elevated in lung cancer patients compared to normal subjects. However, levels of PGI₂ mRNA decreased after cancer treatment. PGI₂ levels were associated with distant metastasis.

Nana-Sinkam et al[90] detected lower levels of PGI₂ synthase mRNA and protein in lung tumor tissue than in normal lung tissue.

Liu et al[91] displayed that PGE₂ levels were higher in lung tumor tissue than in normal lung tissue.

Zhu et al[92] reported that NSCLC cells highly expressed PGE₂ compared to SCLC cells.

McLemore et al[85] found that lung cancer tissue produced more PGE₂ than normal lung tissue.

Honegger et al[93] indicated higher PGE₂ levels in lung cancer patients than in the normal controls.

Hidalgo et al[94] determined elevated plasma PGE₂ levels in NSCLC patients compared to the control group.

Gào et al[95] detected a correlation between urinary 8-iso-PGF_2α levels and lung cancer incidence.

Ma et al[96] showed higher blood 8-iso-PGF_2α levels in patients with lung cancer than in patients with benign lung nodules and patients with chronic obstructive pulmonary disease/asthma.

Stathopoulos et al[97] demonstrated that chemotherapy treatment declined 8-iso-PGF_2α levels in NSCLC patients.

Dalaveris et al[98] determined elevated serum levels of 8-iso-PGF_2α in lung cancer patients compared to healthy controls. Serum 8-iso-PGF_2α levels were higher in patients with advanced stage than in patients with locoregional stage.

Chan et al[99] found elevated 8-iso-PGF_2α levels in exhaled breath condensate (EBC) of NSCLC patients compared to smokers.

The effects and levels of TXs on lung cancer

Table 5 summarizes five studies on the effects of TXs in lung cancer cell lines, including NCI-H23, A549, H157, and PC-9. TXA₂ induces anti-apoptosis, angiogenesis, invasion, cell growth, and proliferation.

Table 5 Effects of thromboxanes on lung cancer.

Factor	Models	Effects	Ref.
Thromboxane A2	NCI-H23 and A549 cell lines	Proliferative	[100]
	A549 cell line	Invasive	[101]
	H157 cell line	Proliferative	[102]
	A549 cell line	Growth and angiogenesis	[103]
	PC-9 and PC-9/CDDP cell lines	Anti-apoptotic	[104]

Huang et al[100] investigated the role of TXA₂ on LUAD cells. TXA₂S blocker furegrelate and TP inhibitor SQ29548 hindered NCI-H23 and A549 cell proliferation. Similarly, TXA₂ modulators PTXA₂ and BM567 inhibited the cell proliferation and arrested the NNK-induced G₂/M phase cell cycle. PTXA₂ exhibited its inhibitory effects by downregulating cyclinB1 and CDK1 expressions. The expression of survivin, an anti-apoptotic protein, was reduced by NS398 and BM567 inhibitors. The TXA₂ agonist U46619 stimulated NCI-H23 cell proliferation inhibited by COX-2 siRNA.

Li and Tai[101] reported that TXA₂ could promote monocyte chemoattractant protein-1 (MCP-1) release from A549 cells, leading to the invasion of lung cancer cells.

Li and Tai[102] demonstrated that TP agonist I-BOP led to a proliferation in H157 cells by inducing Nurr1 gene expression.

Wei et al[103] showed increased tumor growth and angiogenesis in nude mice inoculated with A549-TPα cells. However, the activated TPα signaling cascade could induce VEGF expression.

Fujimura et al[104] examined the effects of TP antagonists, S-1452 and ONO-NT-126, on CDDP-induced apoptosis in PC-9 and PC-9/CDDP cells. TXA₂ blockage enhanced the cell death by inducing ICH-1 L protein expression.

Table 6 summarizes four studies on TX levels in lung cancer models. Both TXA₂ and TXB₂ levels were elevated in lung cancer.

Table 6 Levels of thromboxanes on lung cancer models.

Factor	Models	Levels	Ref.
Thromboxane A2	NCI-H23, NCI-H460, and A549 cell lines	High	[100]
Thromboxane B2	A549 cell line	High	[105]
	NSCLC tissue	High	[106]
	NSCLC patient	High	[107]

NSCLC: Non-small cell lung cancer.

Huang et al[100] determined that COX-2 Levels were abundant in NCI-H23, NCI-H460, and A549 cells compared with normal cells. The specific COX-1 inhibitor SC560 did not significantly suppress TXA₂ production, while the COX-2 inhibitor NS398 caused a decrease in A549 and NCI-H23 cells.

Wei et al[105] detected that I-BOP enhanced TXB₂ levels in A549 cells with transfected TPα. The stimulatory activity of I-BOP was concerned with COX-2 upregulation.

Chen et al[106] found higher TXB₂ and anti-apoptotic protein Bcl-2 Levels in NSCLC tissue than in normal tissue.

Cathcart et al[107] measured elevated TXB₂ levels in NSCLC serum samples compared to control serum samples.

The effects and levels of ETs on lung cancer

Table 7 summarizes three studies on the effects of TXs in A549 and SPC-A1 cancer cell lines. ET-1 is involved in tumor cell proliferation and invasion, and ET-2 exerts anti-apoptotic effects.

Table 7 Effects of endothelins on lung cancer models.

Factor	Models	Effects	Ref.
Endothelin-1	A549 cell line	Proliferative and invasive	[108]
	SPC-A1 cell line	Proliferative	[109]
Endothelin-2	A549 cell line	Anti-apoptotic	[110]

Zhang et al[108] reported that RNA interference-induced ET-1 gene silencing suppressed proliferation and invasion in A549 Lung carcinoma cells. The combination with Endostar, a modified human recombinant endostatin, potentiated those effects. ET-1 silencing increased E-cadherin while decreasing pro-angiogenic VEGF.

Zhang et al[109] showed that ET-1 promoted SPC-A1 cell proliferation by activating the ET-A receptor. However, the ET-1/ET-A receptor signaling enhanced intracellular Ca²⁺ levels via the phosphoinositol/Ca²⁺ pathway and voltage-dependent Ca²⁺ channel. Intracellular Ca²⁺ could contribute to the mitogenic property of ET-1.

Suprapto et al[110] demonstrated that silencing ET-2 reduced proliferation, migration, and invasion and facilitated apoptosis in A549 lung cancer cells. Additionally, ET-2 ablation enhanced E-cadherin while decreasing survivin and X-linked inhibitor of apoptosis.

Table 8 summarizes five studies on ET levels in lung cancer models. Both ET-1 and ET-2 Levels were elevated in lung cancer.

Table 8 Levels of endothelins on lung cancer models.

Factor	Models	Levels	Ref.
Endothelin-1	NSCLC tissue	High	[111]
	COR-L88 and A549 cell lines	High	[112]
	NSCLC patient	High	[113]
	NSCLC patient	High	[114]
Endothelin-2	LUAD tissue	High	[110]

LUAD: Lung adenocarcinoma; NSCLC: Non-small cell lung cancer.

Boldrini et al[111] detected that ET-1, ET-A, and ECE-1 mRNA expressions were more elevated in NSCLC tissue than in control tissue. On the contrary, higher ET-B receptor mRNA expression was in control tissue compared to NSCLC tissue.

Ahmed et al[112] showed that ET-1 mRNA was highly expressed by COR-L88 and A549 cells, comparable to human umbilical vein endothelial cells.

Arun et al[113] determined higher plasma big ET-1 levels in NSCLC patients than in healthy subjects.

Chen et al[114] assessed ET-1 and cancer embryo antigen (CEA) levels in patients with NSCLC using EBC, a non-invasive method. ET-1 and CEA levels were higher in serum and EBC of NSCLC patients than in control subjects. However, ET-1 and CEA levels were more elevated in serum and EBC of patients with stages III and IV lung cancer compared to patients with stages I and II lung cancer.

Suprapto et al[110] presented that ET-2 expression in LUAD tissue was higher than in normal lung tissue.

CONCLUSION

Lung cancer is one of the most frequent cancers globally. Endogenous modulators, such as NO, PGs, TXs, and ETs, are involved in the molecular mechanisms of lung carcinogenesis. This study reviewed 76 studies investigating the effects and levels of NO, PGs, TXs, and ETs on lung cancer. In this context, NO induces lung tumorigenesis. PGD₂ and PGI₂ were low concentrations, whereas PGE₂ and 8-iso-PGF_2α were high concentrations in lung cancer. TXA₂ may contribute to tumor development and progression. Lung cancer cells expressed TXB₂ at high levels. ET-1 and ET-2 exhibit neoplastic effects. Therefore, the endogenous modulators may serve as potential biomarkers for predicting lung carcinogenesis.

However, the variability in the levels and effects of endogenous modulators across lung cancer models may undermine diagnostic accuracy and generalizability. Sample heterogeneity poses a critical barrier to the clinical translation of these endogenous modulators for lung cancer. Further in vivo and in vitro preclinical studies are needed to validate NO, PGD₂, PGI₂, PGE₂, 8-iso-PGF_2α, TXA₂, TXB₂, ET-1, and ET-2 as predictive biomarkers in a real-world setting.

Future therapeutic approaches should target the endogenous modulators in lung cancer treatment. In this regard, a combination with PGD₂/PGI₂ agonists can enhance the tumor-suppressive effects, while a combination with NO/PGE₂/8-iso-PGF_2α/TXA₂/TXB₂/ET-1/ET-2 antagonists can hinder tumor-promoting signaling cascades. Moreover, these combinatorial strategies could be integrated into targeted therapies and immunotherapy to modulate anti-tumor and pro-tumor pathways more effectively.