Squalene Epoxidase Inhibitor Research Articles

Cholesterol inhibition enhances antitumor response of gilteritinib in lung cancer cells.

Repositioning approved antitumor drugs for different cancers is a cost-effective approach. Gilteritinib was FDA-approved for the treatment of FLT3-mutated acute myeloid leukemia in 2018. However, the therapeutic effects and mechanism of Gilteritinib on other malignancies remain to be defined. In this study, we identified that gilteritinib has an inhibitory effect on lung cancer cells (LCCs) without FLT3 mutation in vitro and in vivo. Unexpectedly, we found that gilteritinib induces cholesterol accumulation in LCCs via upregulating cholesterol biosynthetic genes and inhibiting cholesterol efflux. This gilteritinib-induced cholesterol accumulation not only attenuates the antitumor effect of gilteritinib but also induces gilteritinib-resistance in LCCs. However, when cholesterol synthesis was prevented by squalene epoxidase (SQLE) inhibitor NB-598, both LCCs and gilteritinib-resistant LCCs became sensitive to gilteritinib. More importantly, the natural cholesterol inhibitor 25-hydroxycholesterol (25HC) can suppress cholesterol biosynthesis and increase cholesterol efflux in LCCs. Consequently, 25HC treatment significantly increases the cytotoxicity of gilteritinib on LCCs, which can be rescued by the addition of exogenous cholesterol. In a xenograft model, the combination of gilteritinib and 25HC showed significantly better efficacy than either monotherapy in suppressing lung cancer growth, without obvious general toxicity. Thus, our findings identify an increase in cholesterol induced by gilteritinib as a mechanism for LCC survival, and highlight the potential of combining gilteritinib with cholesterol-lowering drugs to treat lung cancer.

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

BackgroundWhile de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood.MethodsWe conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses.ResultsMechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy.ConclusionsThus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies and has a poor prognosis. Disruption of squalene epoxidase (SQLE) has been implicated in metabolic disorders and cancer. However, the role of SQLE as a monooxygenase involved in oxidative stress remains unclear. We analyzed the expression and prognosis of lung adenocarcinoma (LUAD) and LUSC samples from GEO and TCGA databases. The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments. JC-1 assay, flow cytometry, and Western blot were used to show changes in apoptosis after intervention of SQLE. Flow cytometry and fluorescence assay of ROS levels were used to indicate oxidative stress status. We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC. Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUSC cells by inducing apoptosis and reactive oxygen species accumulation. However, depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4. Therefore, prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC. Our study indicates that the low expression of SQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance. In future, the combinational therapy of targeting SQLE and ferroptosis could be a promising approach in treating LUSC.

Squalene Epoxidase: Its Regulations and Links with Cancers.

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

Abstract 1449: Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models

Abstract Breast cancer brain metastasis is one of the most common forms of breast cancer metastasis and a major cause of morbidity and mortality. Patients who develop brain metastases tend to be associated with progressive neurologic deficits and short overall survival, which represents an unmet medical need. Extensive research has been conducted to elucidate the mechanism of cancer metastasis with limited information gained as to how cancer cells extravasate and colonize to the brain. Recently, we identified a novel mechanism by which squalene epoxidase (SQLE), the second rate-limiting enzyme in cholesterol biosynthesis, plays a critical role in the process of breast cancer metastasis to the brain. Thus, toward a better understanding of the underlying molecular mechanisms and applications of molecular target(s) for brain metastasis therapy, murine models were employed for investigation of brain extravasation and colonization with intracardiac or direct intracranial injections of GFP/FLuc-labeled human MDA-MB-231 metastatic breast carcinoma cells. The MDA-MB-231 cells were found to metastasize to the brain and other organs following intracardiac implantation into nude mice and were further isolated from each tissue. Interestingly, the isolated brain-metastasized tumor cells (MDA-MB-231-BrM) exhibited a significant upregulation of SQLE expression when compared with those that metastasized to other distal sites. The essential role of SQLE in the specific steps of the breast cancer-to-brain metastatic process was evaluated by ex vivo immunofluorescence analysis and immunohistochemistry staining of brain slices from the study subjects. Our data demonstrate that high SQLE expression is essential for MDA-MB-231-BrM to extravasate into the parenchyma, as well as the formation of micro- and macro-metastases in the brain. Interestingly, we found that blood vessel co-option and the surrounding neuronal cells play key roles in supporting MDA-MB-231-BrM to develop brain macro-metastases. In vitro blood-brain barrier (BBB) models further demonstrated the critical role of SQLE in promoting tumor cell invasion and penetration through the BBB. To verify SQLE as an oncogenic factor that can be selected as a potential therapeutic target in suppressing breast cancer brain metastasis, we evaluated the inhibitory effects of terbinafine (a SQLE inhibitor) in both the MDA-MB-231-BrM orthotopic and intracardiac mouse models. Pharmacologic inhibition of SQLE by terbinafine suppressed MDA-MB-231-BrM tumor growth at the mammary fat pad and distal metastases to the brain, suggesting that targeting SQLE represents a therapeutic opportunity for breast cancer brain metastasis. Citation Format: Pony Yu-Ling Lee, Kun-Yuan Lin, Chao-Di Chang, Shan-Yun Cheng, Ya-Wen Hung, Chih-Chieh Yang, Yu-Hsien Chang, Chien-Chang Shen, Jia-Yun Yeh, Yung-Lung Yu, Shu-Ping Wang. Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1449.

Knockdown of SQLE promotes CD8+ T cell infiltration in the tumor microenvironment

Cholesterol biosynthesis and metabolism are critical aspects that shape the process of tumor development and associated microenvironmental conditions owing to the ability of cholesterol to drive tumor growth and invasion. Squalene Epoxidase (SQLE) is the second rate-limiting enzyme involved in the synthesis of cholesterol. The functional role of SQLE within the tumor microenvironment, however, has yet to be established. Here we show that SQLE is distinctively expressed across most types of cancer, and the expression level is highly correlated with tumor mutation burden and microsatellite instability. Accordingly, SQLE was identified as a prognostic risk factor in cancer patients. In addition, we observed a negative correlation between SQLE expression and immune cell infiltration across multiple cancers, and murine xenograft model further confirmed that SQLE knockdown was associated with enhanced intratumoral CD8+ T cell infiltration. Using next-generation sequencing, we identified 410 genes distinctively expressed in tumors exhibiting SQLE inhibition. KEGG and GO analysis further verified that SQLE altered the immune response in the tumor microenvironment. Furthermore, we found that the metabolism and translation of proteins is the main binding factor with SQLE. Our findings ascertain that SQLE is a potential target in multiple cancers and suppressing SQLE establishes an essential mechanism for shaping tumor microenvironment.

Thioredoxin domain containing 5 is involved in the hepatic storage of squalene into lipid droplets in a sex-specific way

Hepatic thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family found associated with anti-steatotic properties of squalene and located in the endoplasmic reticulum and in lipid droplets. Considering that the latter are involved in hepatic squalene accumulation, the present research was aimed to investigate the role of TXNDC5 on hepatic squalene management in mice and in the AML12 hepatic cell line. Wild-type and TXNDC5-deficient (KO) mice were fed Western diets with or without 1% squalene supplementation for 6 weeks. In males, but not in females, absence of TXNDC5 blocked hepatic, but not duodenal, squalene accumulation. Hepatic lipid droplets were isolated and characterized using label-free LC-MS/MS analysis. TXNDC5 accumulated in this subcellular compartment of mice receiving squalene and was absent in TXNDC5-KO male mice. The latter mice were unable to store squalene in lipid droplets. CALR and APMAP were some of the proteins that responded to the squalene administration in all studied conditions. CALR and APMAP were positively associated with lipid droplets in the presence of squalene and they were decreased by the absence of TXNDC5. The increased squalene content was reproduced in vitro using AML12 cells incubated with squalene-loaded nanoparticles and this effect was not observed in an engineered cell line lacking TXNDC5. The phenomenon was also present when incubated in the presence of a squalene epoxidase inhibitor, suggesting a mechanism of squalene exocytosis involving CALR and APMAP. In conclusion, squalene accumulation in hepatic lipid droplets is sex-dependent on TXNDC5 that blocks its secretion.

SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway

Pancreatic cancer (PC), a highly lethal malignancy, commonly exhibits metabolic reprogramming that results in therapeutic vulnerabilities. Nevertheless, the mechanisms underlying the impacts of aberrant cholesterol metabolism on PC development and progression remain elusive. In this study, we found that squalene epoxidase (SQLE) is a crucial mediator of cholesterol metabolism in PC growth. We observed a profound upregulation of SQLE in PC tissues, and its high expression was correlated with poor patient outcomes. Our functional experiments demonstrated that SQLE facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in vitro, while promoting tumor growth in vivo. Mechanistically, SQLE was found to have a dual role. First, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and subsequent apoptosis. Second, it enhanced de novo cholesterol biosynthesis and maintained lipid raft stability, thereby activating the Src/PI3K/Akt signaling pathway. Significantly, employing SQLE inhibitors effectively suppressed PC cell proliferation and xenograft tumor growth. In summary, this study reveals SQLE as a novel oncogene that promotes PC growth by mitigating ER stress and activating lipid raft-regulated Src/PI3K/Akt signaling pathway, highlighting the potential of SQLE as a therapeutic target for PC.

Accumulation of squalene in filamentous fungi Trichoderma virens PS1-7 in the presence of butenafine hydrochloride, squalene epoxidase inhibitor: biosynthesis of 13C-enriched squalene.

Squalene is a triterpenoid compound and widely used in various industries such as medicine and cosmetics due to its strong antioxidant and anticancer properties. The purpose of this study is to increase the accumulation of squalene in filamentous fungi using exogeneous butenafine hydrochloride, which is an inhibitor for squalene epoxidase. The detailed settings achieved that the filamentous fungi, Trichoderma virens PS1-7, produced squalene up to 429.93±51.60mg/L after culturing for 7 days in the medium consisting of potato infusion with glucose at pH 4.0, in the presence of 200µm butenafine. On the other hand, no squalene accumulation was observed without butenafine. This result indicated that squalene was biosynthesized in the filamentous fungi PS1-7, which can be used as a novel source of squalene. In addition, we successfully obtained highly 13C-enriched squalene by using [U-13C6]-glucose as a carbon source replacing normal glucose.

Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC.

Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating through a cholesterol-dependent pathway. Comprehensive transcriptomic analysis reveals that SQLE is essential for maintaining c-Myc transcriptional activity by stabilizing the c-Myc protein and averting its ubiquitin-mediated degradation. Mechanistic investigation demonstrates that SQLE inhibition diminishes Akt's binding affinity to lipid rafts via a cholesterol-dependent process, subsequently deactivating lipid raft-localized Akt, reducing GSK-3β phosphorylation at S9, and increasing c-Myc phosphorylation at T58, ultimately leading to c-Myc destabilization. Importantly, employing an Sqle conditional knockout mouse model, SQLE's critical role in HNSCC initiation and progression is established. The preclinical findings demonstrate the potent synergistic effects of combining terbinafine and cisplatin in arresting tumor growth. These discoveries not only provide novel insights into the underlying mechanisms of SQLE-mediated cisplatin resistance and tumorigenesis in HNSCC but also propose a promising therapeutic avenue for HNSCC patients unresponsive to conventional cisplatin-based chemotherapy.

Inhibition of squalene epoxidase linking with PI3K/AKT signaling pathway suppresses endometrial cancer.

Endometrial cancer (EC) is a common malignant tumor that lacks any therapeutic target and, in many cases, recurrence is the leading ca use of morbidity and mortality in women. Widely known EC has a strongly positive correlation with abnormal lipid metabolism. Squalene epoxidase (SQLE), a crucial enzyme in the cholesterol synthesis pathway regulating lipid metabolic processes has been found to be associated with various cancers in recent years. Here, we focused on studying the role of SQLE in EC. Our study revealed that SQLE expression level was upregulated significantly in EC tissues. In vitro experiments showed that SQLE overexpression significantly promoted the proliferation, and inhibited cell apoptosis of EC cells, whereas SQLE knockdown or use of terbinafine showed the opposite results. Furthermore, we found out that the promotional effect of SQLE on the proliferation of EC cells might be achieved by activating the PI3K/AKT pathway. In vivo, studies confirmed that the knockdown of SQLE or terbinafine can observably inhibit tumor growth in nude mice. These results indicate that SQLE may promote the progression of EC by activating the PI3K/AKT pathway. Moreover, SQLE is a potential target for EC treatment and its inhibitor, terbinafine, has the potential to become a targeted drug for EC treatment.

Reliable and rapid identification of terbinafine resistance in dermatophytic nail and skin infections.

Fungal infections are the most frequent dermatoses. The gold standard treatment for dermatophytosis is the squalene epoxidase (SQLE) inhibitor terbinafine. Pathogenic dermatophytes resistant to terbinafine are an emerging global threat. Here, we determine the proportion of resistant fungal skin infections, analyse the molecular mechanisms of terbinafine resistance, and validate a method for its reliable rapid identification. Between 2013 and 2021, we screened 5634 consecutively isolated Trichophyton for antifungal resistance determined by hyphal growth on Sabouraud dextrose agar medium containing 0.2 μg/mL terbinafine. All Trichophyton isolates with preserved growth capacity in the presence of terbinafine underwent SQLE sequencing. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method. Over an 8-year period, the proportion of fungal skin infections resistant to terbinafine increased from 0.63% in 2013 to 1.3% in 2021. Our routine phenotypic in vitro screening analysis identified 0.83% (n = 47/5634) of Trichophyton strains with in vitro terbinafine resistance. Molecular screening detected a mutation in the SQLE in all cases. Mutations L393F, L393S, F397L, F397I, F397V, Q408K, F415I, F415S, F415V, H440Y, or A398 A399 G400 deletion were detected in Trichophyton rubrum. Mutations L393F and F397L were the most frequent. In contrast, all mutations detected in T. mentagrophytes/T. interdigitale complex strains were F397L, except for one strain with L393S. All 47 strains featured significantly higher MICs than terbinafine-sensitive controls. The mutation-related range of MICs varied between 0.004 and 16.0 μg/mL, with MIC as low as 0.015 μg/mL conferring clinical resistance to standard terbinafine dosing. Based on our data, we propose MIC of 0.015 μg/mL as a minimum breakpoint for predicting clinically relevant terbinafine treatment failure to standard oral dosing for dermatophyte infections. We further propose growth on Sabouraud dextrose agar medium containing 0.2 μg/mL terbinafine and SQLE sequencing as fungal sporulation-independent methods for rapid and reliable detection of terbinafine resistance.

The Effect of Terbinafine and Its Ionic Salts on Certain Fungal Plant Pathogens.

Terbinafine, an inhibitor of squalene epoxidase in ergosterol biosynthesis, is chiefly utilized as an antifungal medication with potential uses in pesticide applications. This study explores the fungicidal efficacy of terbinafine against prevalent plant pathogens and confirms its effectiveness. To augment its water solubility, five ionic salts of terbinafine were synthesized by pairing them with organic acids. Among these salts, TIS 5 delivered the most impressive results, amplifying the water solubility of terbinafine by three orders of magnitude and lessening its surface tension to facilitate better dispersion during spraying. The in vivo experiments on cherry tomatoes showed that TIS 5 had a superior therapeutic activity compared to its parent compound and two commonly used broad-spectrum fungicides, pyraclostrobin and carbendazim. The results highlight the potential of terbinafine and its ionic salts, particularly TIS 5, for use as fungicides in agriculture due to their synergistic effects with furan-2-carboxylate.

Targeting squalene epoxidase in breast-to-brain metastasis: A new therapeutic target for brain extravasation and colonization using animal models.

1084 Background: Brain metastasis is the most common malignancy of the central nervous system which causes severe morbidity and mortality in multiple cancer types of patients and represents an unmet medical need. Several critical steps are required for a successful brain metastasis, including local invasion, intravasation, dissemination, extravasation, and colonization. Extensive research has been conducted to elucidate the mechanism of cancer metastasis with limited information toward how cancer cells extravasate and colonize. Methods: To understand the underlying molecular mechanisms and applications of molecular targets for brain metastasis therapy, murine models are employed for investigation of brain extravasation and colonization. To investigate the roles of SQLE in breast-to-brain metastasis in vivo, we silenced SQLE expression directly with lentiviral shRNA in the brain metastatic MDA-MB-231-BR cell line (231-BR/shSQLE) and used 231-BR cells expressing a scramble shRNA (231-BR/shScr) as the control. Brain metastases were induced by intracardiac, orthotopic, or direct intracranial injections of 231-BR/shSQLE or 231-BR/shScr cells into immune deficient mice. The essential roles of SQLE in the specific step(s) of breast-to-brain metastatic process were evaluated by ex vivo immunofluorescence analysis of brain slices from the animals. To verify SQLE as an oncogenic factor that can be selected as a potential therapeutic target in suppressing breast-to-brain metastasis, we evaluated the inhibitory effects of NB-598 (a SQLE inhibitor) in both the 231-BR orthotopic and intracardiac mouse models. Results: Recently, we identified a novel mechanism by which squalene epoxidase (SQLE), the second rate-limiting enzyme in the cholesterol biosynthesis, plays a critical role in the processes of breast cancer metastasized to the brain, especially in brain extravasation and colonization. Interestingly, the pharmacologic inhibition of SQLE has been widely used against fungal infections, and the next-generation SQLE inhibitors have been recently shown to exert an anticancer effect. Our data demonstrated that SQLE is essential for 231-BR cells to extravasate into the parenchyma as well as the formation of micro and macro-metastases in the brain. Interestingly, we found that astrocytes play a key role in supporting 231-BR-developed brain macro-metastasis. In vitro blood-brain barrier (BBB) models further demonstrated the critical roles of SQLE in promoting 231-BR cell invasion and penetration through BBB. Inhibition of SQLE by NB-598 demonstrated anti-tumor proliferation and anti-metastasis. Conclusions: Pharmacologic inhibition of SQLE by NB-598 suppressed 231-BR tumor growth at the mammary fat pad and distal metastases to organs, suggesting that targeting SQLE represents a therapeutic opportunity for breast cancer metastases.

Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF-β/SMAD signalling.

Squalene epoxidase (SQLE) is a key enzyme involved in cholesterol biosynthesis, but growing evidence also reveals that SQLE is abnormally expressed in some types of malignant tumours, even though the underlying mechanism remains poorly understood. Bioinformatics analysis and RNA sequencing were applied to detect differentially expressed genes in clinical hepatocellular carcinoma (HCC). MTT, colony formation, AnnexinV-FITC/PI, EdU, wound healing, transwell, western blot, qRT-PCR, IHC, F-actin, RNA-sequencing, dual-luciferase reporters, and H&E staining were used to investigate the pharmacological effects and possible mechanisms of SQLE. SQLE expression was specifically elevated in HCC, correlating with poor clinical outcomes. SQLE significantly promoted HCC growth, epithelial-mesenchymal transition, and metastasis both in vitro and in vivo. RNA sequencing and functional experiments revealed that the protumourigenic effect of SQLE on HCC was closely related to the activation of TGF-β/SMAD signalling, but the stimulatory effect of SQLE on TGF-β/SMAD signalling and HCC development is critically dependent on STRAP. SQLE expression is well correlated with STRAP in HCC, and further, to amplify TGF-β/SMAD signalling, SQLE even transcriptionally increased STRAP gene expression mediated by AP-2α. Finally, as a chemical inhibitor of SQLE, NB-598 markedly inhibited HCC cell growth and tumour development. Taken together, SQLE serves as a novel oncogene in HCC development by activating TGF-β/SMAD signalling. Targeting SQLE could be useful in drug development and therapy for HCC.

P53 and MYC-regulated squalene epoxidase as Achilles heel in colorectal cancer.

The transcription factors p53 and MYC are often considered non-druggable targets, but their dysregulation can generate new dependencies and treatment opportunities in cancer cells. The p53 and MYC-regulated squalene epoxidase (SQLE) has been identified as a potential Achilles heel in colorectal cancer. This is of great interest because the FDA-approved anti-fungal SQLE inhibitor Terbinafine could be repurposed to treat colorectal cancer patients.

Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis

ObjectiveAberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function...

Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy.

Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.

Antibacterial Effect of Some Eukaryotic Sterol Biosynthesis Inhibitors.

Isoprenoids and their derivatives are building blocks for the synthesis of biomolecules with important biological functions such as cholesterol in eukaryotes and lipid carrier undecaprenol, which is involved in cell wall biosynthesis in bacteria. With the global threat of multidrug-resistant bacteria, there is a need for finding new metabolic targets for killing bacteria. In the present study, we examined the impact of eukaryotic sterol biosynthesis inhibitors on the growth of four pathogenic bacteria. Antibacterial effect of HMG CoA reductase inhibitor (simvastatin), farnesyl pyrophosphate synthase inhibitor (alendronate), squalene epoxidase inhibitor (terbinafine), and lanosterol demethylase inhibitor (ketoconazole) were studied against four pathogenic bacteria: two gram-positive bacteria, Staphylococcus aureus and Enterococcus faecalis and two gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa. Broth microdilution method was used for assessing the antibacterial susceptibility of the components using 96 well plats. MIC and MBC were determined visibly. MIC of Ketoconazole for Staphylococcus aureus and Enterococcus faecalis were 0.166 and 1 mg/mL, respectively. Terbinafine had a weak inhibitory effect on Staphylococcus aureus (MIC: 8 mg/mL). Ketoconazole and terbinafine had no inhibitory effect on gram-negative bacteria. MBC of Simvastatin for both Staphylococcus aureus and Enterococcus faecalis was 0.5 mg/mL and of Alendronate for Pseudomonas aeruginosa was 6.6 mg/mL. Our results show that farnesyl pyrophosphate synthase and class II HMG-CoA reductases inhibitors (ketoconazole and simvastatin) have reasonable antibacterial activity against gram-positive bacteria. These two enzymes provide suitable targets for designing new antibiotics based on modifying the chemical structure of currently used drugs to obtain maximum activity.

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma.

Recently, increasing attention has been paid to the role of Squalene epoxidase (SQLE) in several types of cancers. However, its functional role in tumor progression of head and neck squamous cell carcinoma (HNSCC) is still unclear. We performed bioinformatic analyses and relative experiments to assess the potential mechanism of SQLE-mediated HNSCC malignancy. And the results showed that SQLE was significantly upregulated in tumor samples compared with peritumor samples. Mechanistically, miR-584-5p downregulation may lead to the upregulation of SQLE in HNSCC. Moreover, high SQLE expression in HNSCC was associated with TNM stage, distant metastasis, and poor survival, indicating that SQLE be involved in the progression of HNSCC. Furtherly, SQLE boosted proliferation, migration, invasion of HNSCC cells in vitro and in vivo. Bioinformatic studies showed that PI3K/Akt signaling participated in HNSCC progression mediated by SQLE overexpression, which is confirmed by in vitro and in vivo analysis. Particularly, treatment with terbinafine, an inhibitor of SQLE widely used in the treatment of fungal infections, showed a therapeutic influence on HNSCC. Our findings demonstrate that SQLE plays a vital role in HNSCC progression, providing research evidence for SQLE as a prospective HNSCC therapeutic target and for terbinafine as a candidate drug of HNSCC treatment in the future