Chaetocin enhances tumor necrosis factor‑related apoptosis‑inducing ligand‑mediated apoptosis by enhancing DR5 stabilization and reactive oxygen species generation in human glioblastoma cells

Jung,Hui-Jung; Kim,Jin Kyung; Suh,Seong-Il; Baek,Won-Ki

doi:10.3892/ijo.2025.5753

Chaetocin enhances tumor necrosis factor‑related apoptosis‑inducing ligand‑mediated apoptosis by enhancing DR5 stabilization and reactive oxygen species generation in human glioblastoma cells

Authors:
- Hui-Jung Jung
- Jin Kyung Kim
- Seong-Il Suh
- Won-Ki Baek
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Affiliations: Department of Microbiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
Published online on: May 13, 2025 https://doi.org/10.3892/ijo.2025.5753
Article Number: 47
Copyright: © Jung et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chaetocin, a fungal metabolite, exerts notable antiproliferative effects against solid tumors by triggering apoptosis; however, the mechanisms underlying its effects remain unclear. As tumor necrosis factor (TNF)‑related apoptosis‑inducing ligand (TRAIL) promotes apoptosis in certain types of tumor, the present study aimed to explore the sensitizing effects of chaetocin in TRAIL‑induced apoptosis in human glioblastoma cells and the underlying mechanism. Human glioblastoma cells (U343MG, U87MG, U251MG, and T98G) and embryonic kidney cells (HEK293) were co‑treated with chaetocin and TRAIL, followed by assessment of cell viability. The results from viability and apoptosis assays demonstrated a significant increase in caspase-dependent apoptosis in glioblastoma cells, but not in HEK293 cells, upon co-treatment with chaetocin and TRAIL. Additionally, death receptor 5 (DR5) expression analysis demonstrated that co‑treatment with chaetocin and TRAIL upregulated DR5 expression in a dose‑ and time‑dependent manner by increasing the stability of DR5 on the cell surface. In glioblastoma cells, small interfering RNA‑mediated DR5 knockdown markedly suppressed chaetocin/TRAIL‑induced apoptosis. Moreover, chaetocin enhanced reactive oxygen species (ROS) production, which facilitated TRAIL‑mediated apoptosis by enhancing DR5 upregulation. Thus, chaetocin sensitized the human glioblastoma cell lines U87MG and T98G to TRAIL‑mediated apoptosis by upregulating DR5 expression through ROS-mediated mechanisms. The present findings underscore chaetocin as a potential novel therapeutic agent for glioblastoma.

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1	Hanif F, Muzaffar K, Perveen K, Malhi SM and Simjee ShU: Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 18:3–9. 2017.PubMed/NCBI
2	Shergalis A, Bankhead A III, Luesakul U, Muangsin N and Neamati N: Current challenges and opportunities in treating glioblastoma. Pharmacol Rev. 70:412–445. 2018. View Article : Google Scholar : PubMed/NCBI
3	Dai X, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS and Sethi G: Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp Biol Med (Maywood). 240:760–773. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bin L, Thorburn J, Thomas LR, Clark PE, Humphreys R and Thorburn A: Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. J Biol Chem. 282:28189–28194. 2007. View Article : Google Scholar : PubMed/NCBI
5	Pimentel JM, Zhou JY and Wu GS: The role of TRAIL in apoptosis and immunosurveillance in cancer. Cancers (Basel). 15:27522023. View Article : Google Scholar : PubMed/NCBI
6	Wachmann K, Pop C, van Raam BJ, Drag M, Mace PD, Snipas SJ, Zmasek C, Schwarzenbacher R, Salvesen GS and Riedl SJ: Activation and specificity of human caspase-10. Biochemistry. 49:8307–8315. 2010. View Article : Google Scholar : PubMed/NCBI
7	Deng Y, Lin Y and Wu X: TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/Diablo. Genes Dev. 16:33–45. 2002. View Article : Google Scholar : PubMed/NCBI
8	Meurette O, Rebillard A, Huc L, Le Moigne G, Merino D, Micheau O, Lagadic-Gossmann D and Dimanche-Boitrel MT: TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions. Cancer Res. 67:218–226. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kim B, Seo JH, Lee KY and Park B: Icariin sensitizes human colon cancer cells to TRAIL-induced apoptosis via ERK-mediated upregulation of death receptors. Int J Oncol. 56:821–834. 2020.PubMed/NCBI
10	Manouchehri JM, Turner KA and Kalafatis M: TRAIL-induced apoptosis in TRAIL-resistant breast carcinoma through quercetin cotreatment. Breast Cancer (Auckl). 12:11782234177498552018. View Article : Google Scholar : PubMed/NCBI
11	Liu S, Qiu J, He G, He W, Liu C, Cai D and Pan H: TRAIL promotes hepatocellular carcinoma apoptosis and inhibits proliferation and migration via interacting with IER3. Cancer Cell Int. 21:632021. View Article : Google Scholar : PubMed/NCBI
12	Greiner D, Bonaldi T, Eskeland R, Roemer E and Imhof A: Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol. 1:143–145. 2005. View Article : Google Scholar
13	Han X, Han Y, Zheng Y, Sun Q, Ma T, Zhang J and Xu L: Chaetocin induces apoptosis in human melanoma cells through the generation of reactive oxygen species and the intrinsic mitochondrial pathway, and exerts its anti-tumor activity in vivo. PLoS One. 12:e01759502017. View Article : Google Scholar : PubMed/NCBI
14	Chaib H, Nebbioso A, Prebet T, Castellano R, Garbit S, Restouin A, Vey N, Altucci L and Collette Y: Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1. Leukemia. 26:662–674. 2012. View Article : Google Scholar
15	Liu X, Guo S, Liu X and Su L: Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells. Apoptosis. 20:1499–1507. 2015. View Article : Google Scholar : PubMed/NCBI
16	Jung HJ, Seo I, Jha BK, Suh SI and Baek WK: Miconazole induces autophagic death in glioblastoma cells via reactive oxygen species-mediated endoplasmic reticulum stress. Oncol Lett. 21:3352021. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
18	Yamamoto K, Makino M, Watanapokasin R, Tashiro E and Imoto M: Inostamycin enhanced TRAIL-induced apoptosis through DR5 upregulation on the cell surface. J Antibiot (Tokyo). 65:295–300. 2012. View Article : Google Scholar : PubMed/NCBI
19	Dilshara MG, Jayasooriya RGPT, Molagoda IMN, Jeong JW, Lee S, Park SR, Kim GY and Choi YH: Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca²⁺-CaMKII-Sp1 pathway. Oncotarget. 9:10324–10342. 2018. View Article : Google Scholar : PubMed/NCBI
20	Yodkeeree S, Sung B, Limtrakul P and Aggarwal BB: Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: Evidence for an essential role of reactive oxygen species. Cancer Res. 69:6581–6589. 2009. View Article : Google Scholar : PubMed/NCBI
21	Hori T, Kondo T, Kanamori M, Tabuchi Y, Ogawa R, Zhao QL, Ahmed K, Yasuda T, Seki S, Suzuki K and Kimura T: Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. Cancer Lett. 287:98–108. 2010. View Article : Google Scholar
22	Wang W and El-Deiry WS: Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy. Proc Natl Acad Sci USA. 9:15095–15100. 2003. View Article : Google Scholar
23	Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, Paton AW, Paton JC, Walter P and Ashkenazi A: Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science. 345:98–101. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yue D and Sun X: Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells. Cancer Biol Ther. 20:284–294. 2019. View Article : Google Scholar :
25	Kong F, You H, Zhao J, Liu W, Hu L, Luo W, Hu W, Tang R and Zheng K: The enhanced expression of death receptor 5 (DR5) mediated by HBV X protein through NF-kappaB pathway is associated with cell apoptosis induced by (TNF-α related apoptosis inducing ligand) TRAIL in hepatoma cells. Virol J. 12:1922015. View Article : Google Scholar
26	Sekita S, Yoshihira K, Natori S, Udagawa S, Muroi T, Sugiyama Y, Kurata H and Umeda M: Mycotoxin production by Chaetomium spp and related fungi. Can J Microbiol. 27:766–772. 1981. View Article : Google Scholar : PubMed/NCBI
27	Wang H, Wen C, Chen S, Li W, Qin Q, He L, Wang F, Chen J, Ye W, Li W, et al: ROS/JNK/C-jun pathway is involved in chaetocin induced colorectal cancer cells apoptosis and macrophage phagocytosis enhancement. Front Pharmacol. 12:7293672021. View Article : Google Scholar : PubMed/NCBI
28	Li Z, Huang L, Wei L, Hou Z, Ye W and Huang S: Chaetocin induces caspase-dependent apoptosis in ovarian cancer cells via the generation of reactive oxygen species. Oncol Lett. 18:1915–1921. 2019.PubMed/NCBI
29	Jung HJ, Seo I, Casciello F, Jacquelin S, Lane SW, Suh SI, Suh MH, Lee JS and Baek WK: The anticancer effect of chaetocin is enhanced by inhibition of autophagy. Cell Death Dis. 7:e20982016. View Article : Google Scholar : PubMed/NCBI
30	Holoch PA and Griffith TS: TNF-related apoptosis-inducing ligand (TRAIL): A new path to anti-cancer therapies. Eur J Pharmacol. 625:63–72. 2009. View Article : Google Scholar : PubMed/NCBI
31	LeBlanc HN and Ashkenazi A: Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10:66–75. 2003. View Article : Google Scholar : PubMed/NCBI
32	Wang S and El-Deiry WS: TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 22:8628–8633. 2003. View Article : Google Scholar : PubMed/NCBI
33	Son YG, Kim EH, Kim JY, Kim SU, Kwon TK, Yoon AR, Yun CO and Choi KS: Silibinin sensitizes human glioma cells to TRAIL-mediated apoptosis via DR5 up-regulation and down-regulation of c-FLIP and survivin. Cancer Res. 67:8274–8284. 2007. View Article : Google Scholar : PubMed/NCBI
34	Senbabaoglu F, Cingoz A, Kaya E, Kazancioglu S, Lack NA, Acilan C and Bagci-Onder T: Identification of mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. Cancer Biol Ther. 17:546–557. 2016. View Article : Google Scholar : PubMed/NCBI
35	Liu PC, Lu G, Deng Y, Wang CD, Su XW, Zhou JY, Chan TM, Hu X and Poon WS: Inhibition of NF-κB pathway and modulation of MAPK signaling pathways in glioblastoma and implications for lovastatin and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) combination therapy. PLoS One. 12:e01711572017. View Article : Google Scholar
36	Аrtykov АА, Belov DA, Shipunova VO, Trushina DB, Deyev SM, Dolgikh DA, Kirpichnikov MP and Gasparian ME: Chemotherapeutic agents sensitize resistant cancer cells to the DR5-specific variant DR5-B more efficiently than to TRAIL by modulating the surface expression of death and decoy receptors. Cancers (Basel). 12:11292020. View Article : Google Scholar : PubMed/NCBI
37	Gibson SB, Oyer R, Spalding AC, Anderson SM and Johnson GL: Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Mol Cell Biol. 20:205–212. 2000. View Article : Google Scholar
38	Ozyerli-Goknar E, Sur-Erdem I, Seker F, Cingöz A, Kayabolen A, Kahya-Yesil Z, Uyulur F, Gezen M, Tolay N, Erman B, et al: The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma. Cell Death Dis. 10:8942019. View Article : Google Scholar : PubMed/NCBI
39	Mandal PK, Schneider M, Kölle P, Kuhlencordt P, Förster H, Beck H, Bornkamm GW and Conrad M: Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation. Cancer Res. 70:9505–9514. 2010. View Article : Google Scholar : PubMed/NCBI
40	Sporn MB and Liby KT: NRF2 and cancer: The good, the bad and the importance of context. Nat Rev Cancer. 12:564–571. 2012. View Article : Google Scholar : PubMed/NCBI
41	Yamaguchi H and Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 279:45495–45502. 2004. View Article : Google Scholar : PubMed/NCBI
42	Taniguchi H, Yoshida T, Horinaka M, Yasuda T, Goda AE, Konishi M, Wakada M, Kataoka K, Yoshikawa T and Sakai T: Baicalein overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance via two different cell-specific pathways in cancer cells but not in normal cells. Cancer Res. 68:8918–8927. 2008. View Article : Google Scholar : PubMed/NCBI
43	Shin D, Kwon HY, Sohn EJ, Nam MS, Kim JH, Lee JC, Ryu SY, Park B and Kim SH: Upregulation of death receptor 5 and production of reactive oxygen species mediate sensitization of PC-3 prostate cancer cells to TRAIL induced apoptosis by vitisin A. Cell Physiol Biochem. 36:1151–1162. 2015. View Article : Google Scholar : PubMed/NCBI