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Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells

TAIRA HIROSE, YUKI KUNISADA, KOICHI KADOYA, HIROKI MANDAI, YUMI SAKAMOTO, KYOICHI OBATA, KISHO ONO, HIROAKI TAKAKURA, KAZUHIRO OMORI, SHOGO TAKASHIBA, SEIJI SUGA and SOICHIRO IBARAGI
Cancer Genomics & Proteomics September 2024, 21 (5) 464-473; DOI: https://doi.org/10.21873/cgp.20464

Abstract

Background/Aim: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. Materials and methods: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. Results: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. Conclusion: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.

Key Words:

Malignant melanomas originate from melanocytes in the basal layer of the epidermis. Despite being easily detectable on the skin, malignant melanoma is a high-grade tumor characterized by poor prognosis primarily because of its propensity for early lymphatic and hematogenous metastases (1, 2). This tumor type exhibits low radiosensitivity, rendering surgery and pharmacotherapy as the primary treatment modalities. NCCN guideline insights for cutaneous melanoma (version 2.2021) advocate excision as the primary treatment for malignant melanoma (3). However, this approach often results in significant functional and aesthetic defects. The therapeutic landscape for malignant melanoma has evolved considerably with the introduction of immune checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1 antibodies, and molecularly targeted agents such as BRAF inhibitors (4-6).

Angiogenin (ANG), an angiogenic factor initially identified in the culture supernatant of the human colon cancer cell line HT-29 (7), has recently been implicated in the autocrine stimulation of cancer cell proliferation (8). In malignant melanoma cells, ANG is directly involved in tumor proliferation and angiogenesis. Studies have shown that endogenous ANG expression enhances basic fibroblast growth factor (bFGF) expression (9). Consequently, the selective inhibition of ANG could simultaneously regulate angiogenesis and tumor cell proliferation. ANG migrates to the nucleus, accumulates in the nucleolus, and binds to the promoter region of ribosomal DNA (rDNA). This binding enhances ribosomal RNA (rRNA) transcription, thereby promoting cell proliferation (10). The ANG receptor, identified as Plexin-B2 (PLXNB2) in 2017 (11), also serves as a receptor for the neuroaxonal guidance factor semaphorin (12). The discovery of the PLXNB2 receptor marks a significant advancement in ANG functional analysis, a field that has previously seen limited progress.

Terrein (C8H10O3), with a molecular weight of 154.17, is an organic compound isolated as a metabolite from Aspergillus terreus, a species of the Aspergillus genus (13). This compound exhibits diverse biological activities, including antibacterial properties, inhibition of melanin production in melanocytes (14-16), suppression of keratinocyte proliferation (17), and reduction of ANG production in prostate cancer cells (18). However, the pharmacological effects of natural terrein, which is extractable only in minute amounts from large quantities of fungi, remain largely unexplored. Mandai et al. developed a method for the complete chemical synthesis of terrein and verified that the structure of synthetic terrein is identical to that of its natural counterpart (19). In this study, we explored the anti-tumor effects of inhibiting ANG production in malignant melanoma cells using synthetic terrein supplied by the Mandai research group and investigated the underlying mechanisms.

Materials and Methods

Cultured cell lines. The human malignant melanoma cell line A375 (The European Collection of Authenticated Cell cultures, mouse malignant melanoma cell line B16 (Japanese Collection of Research Bioresources Cell Bank), human melanocytes (normal human melanocytes, NHEM-Ad: Lonza), and human gingival epithelium progenitors (HGEPp, CELLnTEC, Bern, Switzerland) were used. Malignant melanoma cell lines were cultured in a 1:1 mixture of Dulbecco’s modified Eagle’s medium and Ham’s F-12 medium (DMEM/F12; Invitrogen Corp, Grand Island, NY, USA) supplemented with 10% deactivated fetal bovine serum (FBS; JRH Bioscience, Lenexa, KS, USA) and 1% penicillin-streptomycin solution (Gibco, NY, USA), maintained at 37°C in 5% CO2. Melanocyte Growth Medium-4 (MGM-4; Lonza, Basel, Switzerland) was used for NHEM-Ad cells, and epidermal keratinocyte medium (CnT-57; CELLnTEC) for HGEPp was used under the same conditions.

Synthesis of terrain. Terrein (Figure 1) was synthesized organochemically using the Altenbach’s method (20), as provided by Dr. Hiroki Mandai of the Faculty of Health Sciences, Gifu University of Medical Sciences (19). The structure of the synthesized terrein was confirmed using 1H and 13C nuclear magnetic spectroscopy. Its molecular weight was verified using high-resolution mass spectrometry. The optical purity (>98% ee) was confirmed using high-performance liquid chromatography. Comparison with natural extracts established that the synthesized terrein was the same structure as the natural product.

Figure 1.
Figure 1.

Structural formula of terrein. An organic compound with a molecular weight of 154.17 isolated as a metabolite of the fungus Aspergillus terreus.

Cell proliferation assay. To assess terrein’s effect on malignant melanoma cells, A375 and B16 cells were cultured with 20 μM terrein. Cell counts were measured at 24, 72, 120, and 168 h using a disposable cell-counting plate (Burker-Turk Type; WATSON BIO LAB, San Diego, CA, USA).

Cytotoxicity test. The cytotoxicity of terrein was evaluated using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium Bromide (MTT) assay with NHEM-Ad and HGEPp using the MTT Cell Proliferation Assay Kit (Cayman). A total of 1×105 cells were seeded into 96-well plates and treated with 20 μM of terrein. After reaching subconfluency, the MTT solution was added, and the absorbance was measured at 570 nm.

Wound healing assay. Cell motility was assessed using a wound healing assay. A375 cells were cultured in DMEM/F12 containing 10% FBS in 6-well plates until they reached subconfluency. After 24 h in DMEM/F12 supplemented with 0.5% FBS, a ~1 mm wide wound was created. Post 20 μM terrein addition, the wound area was measured after 10 h using Image J software (version 1.43r, NIH, Bethesda, MD, USA).

Cell migration assay. Cell migration was examined using a 24-well cell culture insert (BD Falcon, Franklin Lakes, NJ, USA). A375 cells (1.0×105) in DMEM/F12 with 20 μM terrein were placed on the insert’s upper layer. The lower layer contained DMEM/F12 supplemented with 10% FBS. After 24 hours, cells passing through the 8 μm pore membrane were fixed using Diff-Quik (International Reagent Co., Ltd., Kobe, Japan) and stained with Giemsa. The stained cells were then enumerated.

Cell invasion assay. The invasion ability was evaluated using a Matrigel-coated 24-well plate (Corning, Corning, NY, USA). A375 cells (1.0×105) were seeded on the upper layer. After 24 h, the cells penetrating the Matrigel and membrane were stained in a manner similar to that used in the migration assay.

Western blotting. Proteins from A375 cells (1.0×105) seeded in 60 mm dishes with DMEM/F12 and 10% FBS were harvested after terrein exposure (0, 24, or 48 h). Quantification was performed using the BCA Protein Assay Kit (Pierce, Thermo Fisher Scientific, Inc., Waltham, MA, USA). Proteins (30 or 50 μg) were resolved on a 12% SDS-PAGE gel and transferred onto a membrane. Blocking was done with 5% skimmed milk, followed by overnight incubation with primary antibodies, anti-ANG (Santa Cruz Biotechnology, Santa Cruz, CA, USA, sc-9044), anti-PLXNB2 (Proteintech, Rosemont, IL, USA, 10602-1-AP), anti-Bcl-2 (Cell Signaling Technology, Danvers, MA, USA 15071), anti-Nf-Embedded Imageb (Cell Signaling Technology, 8242), anti-Caspase-3 (Cell Signaling Technology, 9662), and anti-Cleaved Caspase-3 (Cell Signaling Technology, 9661), diluted 1:1000 in skim milk. HRP-conjugated secondary antibodies were then added. Bands were visualized using a ChemiDoc MP system (Bio-Rad Laboratories, Hercules, CA, USA) with ImageJ software for density analysis.

ELISA assay. ANG protein contents in culture supernatants obtained from A375 cells treated with 20 μM terrein for 24 h, 48 h, 72 h, 96 h, and 120 h were quantified using the Human ANG ELISA kit (R&D system Inc, Minneapolis, MN, USA).

Ribosome biosynthesis measurement. A375 cells on glass slides (Cultureslides, BD Falcon) were treated with 20 μM terrein for 24 h. AgNOR staining was performed to assess the ribosomal biosynthesis. The cells were fixed in methanol/acetic acid, stained with a gelatin-formic acid-silver nitrate solution, and mounted. Cells with AgNOR-positive nuclei were counted.

In vivo assay. BALB/c-nu/nu nude mice (Charles River) were subcutaneously transplanted with 1×106 A375 cells. Terrein (30 mg/kg) or PBS (control) was administered intraperitoneally twice a week from the second week. After 5 weeks, the mice were euthanized using carbon dioxide gas, and the tumors were excised and analyzed. Tumor volume and vasculature parameters were measured using ImageJ. This study complied with the guidelines of the Animal Experiment Committee of the Okayama University (OKU-2018359).

TUNEL assay. The excised tumors were fixed, dehydrated, and embedded in paraffin. Apoptosis was detected using a DeadEnd Fluorometric TUNEL System (Promega, Madison, WI, USA). The analysis was performed using the ImageJ software.

Immunohistochemical staining. The tissue sections were deparaffinized, antigen-activated, and peroxidase-blocked. Anti-ANG (ab189207; Abcam, Cambridge, MA, USA) and the VECTASTAIN Elite ABC Kit (Vector Lab, Burlingame, CA, USA) were used for staining, followed by ImmPACT DAB substrate application. ImageJ was used for the density analysis.

Statistical analysis. Data were analyzed using Welch’s test for analysis between two groups. Results are expressed as mean±standard deviation (SD). Values of p<0.05 were considered statistically significant.

Results

Terrein inhibits proliferation of malignant melanoma cells. To assess the ability of terrein to inhibit tumor cell proliferation, we treated A375 and B16 cell cultures with terrein and monitored the cell counts over time. In both cell lines, terrein significantly inhibited cell proliferation compared with the control group at three days post-treatment (Figure 2A). To determine whether this effect was attributable to terrein cytotoxicity, we conducted MTT assays using NHEM-Ad and HGEPp cells treated with terrein. There was no significant difference in cytotoxicity between the terrein-treated and control groups (Figure 2B).

Figure 2.
Figure 2.
Figure 2.

Effect of terrein on malignant melanoma cells and normal cells. (A) Proliferative potential was examined using A375 and B16 cells (n=6). The control group exhibited significant cell proliferation, whereas cell proliferation in the terrein-treated group was suppressed. (B) NHEM-Ad and HGEPp cells were seeded, and the cytotoxicity of terrein was examined using the MTT assay (n=4). In both cell lines, there was no significant difference in cell viability between the terrein-treated and control groups. (C) Wound motility of A375 and B16 cells (n=4). Solid lines indicate lines at the beginning of the scratch assay. Dotted lines indicate areas without cells after 10 h. The wound area was almost completely closed after 10 h in the control group, whereas wound closure was significantly inhibited in the terrein-treated group. (D) Invasion ability was evaluated using A375 cells (n=6). invasion was found to be inhibited to a greater extent in the terrain group than in the control group. Scale bar=500 μm. **p<0.01 and ***p<0.001 using Welch’s test.

Additionally, a wound-healing assay with A375 cells revealed that terrein significantly reduced cell motility, and wound closure was 90.7% in the control group versus 57.4% in the terrein-treated group at 10 h post-treatment (Figure 2C). The invasion assay using A375 cells demonstrated that terrein significantly suppressed cell invasion (Figure 2D).

Terrein suppresses ANG production in tumor cells. Given the reports of terrein-mediated inhibition of ANG production in prostate cancer, we evaluated its effect on ANG production in tumor cells. ELISA results showed a decrease in ANG production over time in terrein-treated A375 cells (Figure 3A). Western blotting confirmed that ANG expression was significantly lower in the terrein-treated group compared to the control group (Figure 3B). In contrast, the expression of Plexin-B2 (PLXNB2), an ANG receptor, showed no significant differences between the treated and control groups over time. PLXNB2 expression in A375 cells was validated using HUVEC and RAW264.7 as positive controls (Figure 3C). A notable reduction in AgNOR-positive cells in the terrein-treated group suggested that terrein inhibited ribosome biosynthesis in A375 cells (Figure 3D).

Figure 3.
Figure 3.

Effect of terrein on Angiogenin expression in A375 cells. (A) Terrein significantly suppressed the expression of Angiogenin and Plexin-B2 in A375 cells. After 48 h, angiogenin expression was significantly suppressed in the terrein-treated group (n=6). (B) Western blot analysis showing a decrease in ANG expression and no difference in Plexin-B2 expression. Plexin-B2 expression was confirmed in A375 using HUVEC; RAW264.7 was used as a positive control. (C) 20 μM of Terrein was added, and AgNOR staining was performed 24 hours later (n=6). The number of stained AgNOR-positive nuclei was significantly reduced in the terrein-treated group. Scale bar=10μm. ***p<0.001 using Welch’s test.

Terrein inhibits tumor growth in mouse models. We transplanted A375 cells into 5-week-old male nude mice to explore the potential of terrein in inhibiting tumor growth. The terrain administration significantly inhibited tumor growth (Figure 4A). There was no significant difference in the body weight between the terrain-treated and control groups (Figure 4B). Analysis of tumor angiogenesis, a known function of ANG, showed significant suppression in the terrein-treated group. Angiogenesis metrics, including the number of blood vessels, vessel length, and vessel area, were markedly lower in the terrein-treated group (Figure 4C).

Figure 4.
Figure 4.

Effect of terrein on an animal model of mouse tumor transplantation. To examine the effects of terrein, 1×106 A375 cells were transplanted into the dorsal subcutaneous region of nude mice (n=5). *p<0.05, **p<0.01 and ***p<0.001 using Welch’s test. (A) The increase in tumor size was gradually suppressed in the terrein-treated group, and a significant difference was observed on day 17 after terrein administration. (B) Mouse body weight at the time of terrain administration. No significant differences were found between the two groups (n=5). (C) The epidermis adhering to the tumors excised from mice was removed, and the number, area, and length of the blood vessels running on the inner surface were analyzed (n=5). The number, length, and area of the blood vessels were significantly lower in the group administered with the terrain compared to the control group.

Terrein decreases ANG production in tumors and induces apoptosis of tumor cells. Immunohistochemical staining of tumor tissues revealed a significant decrease in ANG production in the terrein-treated group (Figure 5A). TUNEL staining of tissue sections indicated a significant increase in the number of apoptosis-positive cells in the terrein-treated tumors (Figure 5B).

Figure 5.
Figure 5.

Effect of Terrein on ANG expression and apoptosis induction. Immunohistochemical staining with an angiogenin antibody and TUNEL assay were performed on sections of tumor tissue removed from mice (n=6). (A) Immunohistochemical staining showed that the number of angiogenin-positive cells was significantly lower in the terrein-treated group than in the control group. Scale bar=500 μm. (B) The number of apoptotic cells in the TUNEL assay was significantly higher in the terrein-treated group than in the control group. Scale bar=100 μm. *p<0.05 and **p<0.01 using Welch’s test.

Terrein induces apoptosis in tumor cells. To determine whether terrein directly induces apoptosis, we analyzed the proteins from terrein-treated cells by western blotting. While no significant difference in Bcl-2 and NF-kb expression was observed at 24 h, a notable decrease was evident at 48 h. Conversely, cleaved-caspase 3 levels significantly increased as early as 24 h in the terrein-treated group (Figure 6).

Figure 6.
Figure 6.

Effect of Terrein on apoptosis Induction in A375 cells. The effect of terrein on the induction of apoptosis in A375 cells was examined, and Bcl-2 expression was suppressed after 48 h in the terrein-treated group. The expression of Bcl-2 was suppressed in the terrein-treated group at 48 h, whereas the expression of pro-caspase3 did not differ between the groups at 24 h and 48 h.

Discussion

Terrein, isolated from a fungus of the genus Aspergillus in 1935 (13), has been shown to exhibit various biological activities. Notably, it significantly inhibits melanin production in melanocytes, making it a potential agent for skin whitening in dermatology (14-16). Terrein’s antitumor effects have been reported in several cancers including cervical, breast, lung, ovarian, and prostate cancers (18, 21). This study investigated terrein’s antitumor effects on melanoma cells, alongside its impact on melanocytes, and gingival epithelial progenitor cells. Terrein had negligible effects on the proliferation of melanocytes and gingival epithelial progenitor cells but significantly inhibited the proliferation, motility, migration, and invasion of melanoma cells by approximately 70%, 36%, 99%, and 87%, respectively.

ANG, initially identified as an angiogenic factor, also acts autocrinally on cancer cells to enhance rRNA transcription and cell proliferation (8). The rate of cell proliferation is closely linked to the rate of intracellular protein synthesis, which is stringently regulated by ribosome biosynthesis. The rate-limiting step in this process is rRNA transcription, which is promoted by ANG (10). The nucleolar organizer region (NOR), where rDNA forms a loop structure, is a key site for rRNA transcription and ribosome biosynthesis (22). AgNOR staining, which targets NOR-associated proteins, is indicative of ribosome biogenesis and correlates with the cell proliferative potential (23, 24). In our study, terrein reduced the number of AgNOR dots in the nucleus, suggesting that it inhibited ribosome biosynthesis in malignant melanoma cells. Terrein also suppressed ANG production in prostate cancer cells (18). We extended this finding to malignant melanoma cells by observing the suppressive effect of terrein on both cytoplasmic and supernatant ANG levels as well as on PLXNB2 expression.

The observed suppression of malignant melanoma cell activity by terrein can be attributed to reduced ANG expression and a consequent decline in ribosome biosynthesis. ANG regulates the motility, migration, and invasive potential of vascular endothelial cells (25). It has been demonstrated to form a complex with actin on endothelial cell surfaces, activate tissue plasminogen activators, and induce plasmin synthesis, thereby degrading the extracellular matrix and enhancing the invasive potential (26-28). Our results suggest that terrein inhibits these ANG-mediated effects in malignant melanoma cells. The recent development of a synthetic terrein route by Mandai et al., which enables mass production, has facilitated in vivo studies that were previously limited owing to the need for large quantities of terrein (19). Shibata et al. demonstrated the antitumor effects of synthetic terrein in an oral cancer cell model using thymus-deficient mice (29). In the present study, terrein suppressed tumor formation by approximately 46% and reduced tumor angiogenesis in a mouse model of malignant melanoma.

Immunohistochemical analysis of the tumor tissues confirmed a reduction in ANG expression, corroborating the in vitro findings. TUNEL assays revealed a significant increase in apoptosis in terrein-treated tumor tissues. Furthermore, in vitro experiments showed that terrein activates caspase 3, suppresses the expression of the anti-apoptotic protein Bcl-2, and induces apoptosis. ANG is known to regulate neuronal survival and is implicated in amyotrophic lateral sclerosis (ALS) (30-33). It has been reported to modulate expression of various apoptotic and anti-apoptotic genes (33-35). Terrain induces apoptosis in tumor cells by inhibiting the anti-apoptotic effects of ANG. This finding is consistent with observations in breast cancer and cervical cancer cells. This study suggests that by inhibiting ANG, terrein could be a novel therapeutic agent for malignant melanoma, targeting both angiogenesis and inducing apoptosis in tumor cells.

Conclusion

We investigated the antitumor effects of chemically synthesized terrein on malignant melanoma. Our study demonstrated that terrein exerts antitumor effects on tumor cells by inhibiting ANG production, ribosome biogenesis, and angiogenesis. In a mouse model, terrein significantly suppressed tumor growth without affecting the body weight of the mice and increased apoptosis of tumor cells. These findings suggest that chemically synthesized terrein can be mass-produced and has the potential to be a novel antitumor drug candidate for malignant melanoma.

Acknowledgements

We thank Ms. Kazuko Funakoshi for technical assistance.

Footnotes

  • Conflicts of Interest

    None.

  • Authors’ Contributions

    T. Hirose collected and analyzed the data, performed the experiments, including immunohistochemical staining, and prepared the manuscript. K. Kuhisada and K. Kadoya contributed to the data analysis and final draft of the manuscript. Y. Sakamoto, K. Obata, K. Ono, H. Takakura, K. Omori, and S. Takashiba contributed to the data collection and writing of the manuscript. Mandai and Suga provided the terrain for the experiments. S. Ibaragi corrected and approved the manuscript. All the Authors have read and approved the final version of the manuscript.

  • Funding

    This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grants-in-Aid for Scientific Research (23K27790).

  • Received May 2, 2024.
  • Revision received June 16, 2024.
  • Accepted June 19, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Terrein Exhibits Anti-tumor Activity by Suppressing Angiogenin Expression in Malignant Melanoma Cells
TAIRA HIROSE, YUKI KUNISADA, KOICHI KADOYA, HIROKI MANDAI, YUMI SAKAMOTO, KYOICHI OBATA, KISHO ONO, HIROAKI TAKAKURA, KAZUHIRO OMORI, SHOGO TAKASHIBA, SEIJI SUGA, SOICHIRO IBARAGI
Cancer Genomics & Proteomics Sep 2024, 21 (5) 464-473; DOI: 10.21873/cgp.20464
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