MG132 induces cell type‑specific anticancer effects in uterine leiomyosarcoma cell lines

Joung,Hosouk; Seo,Suho; Liu,Hyunju

doi:10.3892/mmr.2025.13524

MG132 induces cell type‑specific anticancer effects in uterine leiomyosarcoma cell lines

Authors:
- Hosouk Joung
- Suho Seo
- Hyunju Liu
View Affiliations

Affiliations: Research Institute of Medical Sciences, Chonnam National University Medical School, Hwasun‑eup, Jeollanam‑do 58128, Republic of Korea, Department of Food and Drug, Chosun University Graduate School, Gwangju 61452, Republic of Korea, Department of Obstetrics and Gynecology, Chosun University College of Medicine, Gwangju 61452, Republic of Korea
Published online on: April 10, 2025 https://doi.org/10.3892/mmr.2025.13524
Article Number: 159
Copyright: © Joung et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Uterine leiomyosarcoma (Ut‑LMS) is a rare and aggressive malignant tumor with limited therapeutic options. Therefore, exploration of novel treatment strategies is necessary. MG132 is a potent proteasome inhibitor that has shown promising potential in cancer therapy by inducing apoptosis through disruption of protein homeostasis. Despite its promising applications in various cancers, its effects on Ut‑LMS remains largely unexplored. Therefore, the present study investigated the effects of MG132 on Ut‑LMS cell lines (SK‑LMS‑1, SK‑UT‑1 and SK‑UT‑1B) in terms of cytotoxicity, apoptosis induction, cell cycle progression, autophagy and reactive oxygen species (ROS) production. Treatment with MG132 (0‑2 µM for 24 h) induced a dose‑dependent reduction in cell viability across all three cell lines, and the lactate dehydrogenase release assays confirmed membrane damage. Moreover, apoptosis induction was assessed using annexin V and 7‑AAD staining, which revealed dose‑dependent apoptosis in all three cell lines. Western blot analysis revealed increased cleaved poly‑adenosine diphosphate ribose polymerase and caspase‑3 levels, thereby indicating activation of the apoptotic pathway in response to MG132 treatment. MG132 also induced G₂/M phase arrest in SK‑LMS‑1 and SK‑UT‑1 cells and altered the expression of cell cycle regulatory proteins, such as p21, p27 and p53. Furthermore, MG132 promoted autophagy in all three cell lines by increasing light chain 3 II levels. ROS levels remained unchanged in SK‑LMS‑1 cells but increased in SK‑UT‑1B and SK‑UT‑1 cells. Furthermore, the ROS scavenger N‑acetylcysteine effectively reduced MG132‑induced apoptosis in SK‑UT‑1 cells. These findings highlight the cytotoxicity of MG132 in Ut‑LMS cells, emphasize its potential as a therapeutic agent for Ut‑LMS, provide insights into its mechanisms of action, and suggest possible strategies for improving treatment efficacy.

View Figures

View References

1	Byar KL and Fredericks T: Uterine leiomyosarcoma. J Adv Pract Oncol. 13:70–76. 2022. View Article : Google Scholar : PubMed/NCBI
2	Ahuja A, Agarwal P, Sardana R and Bhaskar S: Extensively metastasizing leiomyosarcoma: A diagnostic challenge. J Midlife Health. 8:148–150. 2017.PubMed/NCBI
3	Chapel DB, Sharma A, Lastra RR, Maccio L, Bragantini E, Zannoni GF, George S, Quade BJ, Parra-Herran C and Nucci MR: A novel morphology-based risk stratification model for stage I uterine leiomyosarcoma: An analysis of 203 cases. Mod Pathol. 35:794–807. 2022. View Article : Google Scholar : PubMed/NCBI
4	Chapel DB, Nucci MR, Quade BJ and Parra-Herran C: Epithelioid leiomyosarcoma of the uterus: Modern outcome-based appraisal of diagnostic criteria in a large institutional series. Am J Surg Pathol. 46:464–475. 2022. View Article : Google Scholar : PubMed/NCBI
5	Menon G, Mangla A and Yadav U: Leiomyosarcoma. StatPearls [Internet]. StatPearls Publishing; Treasure Island, FL: 2024
6	Soares Queirós C, Filipe P and Soares de Almeida L: Cutaneous leiomyosarcoma: A 20-year retrospective study and review of the literature. An Bras Dermatol. 96:278–283. 2021. View Article : Google Scholar : PubMed/NCBI
7	Bathan AJ, Constantinidou A, Pollack SM and Jones RL: Diagnosis, prognosis, and management of leiomyosarcoma: Recognition of anatomic variants. Curr Opin Oncol. 25:384–389. 2013. View Article : Google Scholar : PubMed/NCBI
8	Giannini A, Golia D'Augè T, Bogani G, Laganà AS, Chiantera V, Vizza E, Muzii L and Di Donato V: Uterine sarcomas: A critical review of the literature. Eur J Obstet Gynecol Reprod Biol. 287:166–170. 2023. View Article : Google Scholar : PubMed/NCBI
9	Giannini A, Cuccu I, D'Auge TG, De Angelis E, Laganà AS, Chiantera V, Caserta D, Vitale SG, Muzii L, D'Oria O, et al: The great debate: Surgical outcomes of laparoscopic versus laparotomic myomectomy. A meta-analysis to critically evaluate current evidence and look over the horizon. Eur J Obstet Gynecol Reprod Biol. 297:50–58. 2024. View Article : Google Scholar : PubMed/NCBI
10	Kyriazoglou A, Liontos M, Ntanasis-Stathopoulos I and Gavriatopoulou M: The systemic treatment of uterine leiomyosarcomas: A systematic review. No news is good news? Medicine (Baltimore). 100:e253092021.PubMed/NCBI
11	Bhat SA, Vasi Z, Adhikari R, Gudur A, Ali A, Jiang L, Ferguson R, Liang D and Kuchay S: Ubiquitin proteasome system in immune regulation and therapeutics. Curr Opin Pharmacol. 67:1023102022. View Article : Google Scholar : PubMed/NCBI
12	Nunes AT and Annunziata CM: Proteasome inhibitors: Structure and function. Semin Oncol. 44:377–380. 2017. View Article : Google Scholar : PubMed/NCBI
13	Ji MM, Lee JM, Mon H, Xu J, Tatsuke T and Kusakabe T: Proteasome inhibitor MG132 impairs autophagic flux through compromising formation of autophagosomes in Bombyx cells. Biochem Biophys Res Commun. 479:690–696. 2016. View Article : Google Scholar : PubMed/NCBI
14	Momose I and Kawada M: The therapeutic potential of microbial proteasome inhibitors. Int Immunopharmacol. 37:23–30. 2016. View Article : Google Scholar : PubMed/NCBI
15	Guo N and Peng Z: MG132, a proteasome inhibitor, induces apoptosis in tumor cells. Asia Pac J Clin Oncol. 9:6–11. 2013. View Article : Google Scholar : PubMed/NCBI
16	Bulangalire N, Claeyssen C, Agbulut O and Cieniewski-Bernard C: Impact of MG132 induced-proteotoxic stress on αB-crystallin and desmin phosphorylation and O-GlcNAcylation and their partition towards cytoskeleton. Biochimie. 226:121–135. 2024. View Article : Google Scholar : PubMed/NCBI
17	La Frazia S, Amici C and Santoro MG: Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: Role of nuclear factor-kappaB. Antivir Ther. 11:995–1004. 2006. View Article : Google Scholar : PubMed/NCBI
18	Ortiz-Lazareno PC, Hernandez-Flores G, Dominguez-Rodriguez JR, Lerma-Diaz JM, Jave-Suarez LF, Aguilar-Lemarroy A, Gomez-Contreras PC, Scott-Algara D and Bravo-Cuellar A: MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: Involvement of nuclear factor-kappaB and activator protein-1. Immunology. 124:534–541. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kaplan GS, Torcun CC, Grune T, Ozer NK and Karademir B: Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect. Free Radic Biol Med. 103:1–13. 2017. View Article : Google Scholar : PubMed/NCBI
20	Manasanch EE and Orlowski RZ: Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 14:417–433. 2017. View Article : Google Scholar : PubMed/NCBI
21	Goldberg AL: Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol. 199:583–588. 2012. View Article : Google Scholar : PubMed/NCBI
22	Maki RG, Kraft AS, Scheu K, Yamada J, Wadler S, Antonescu CR, Wright JJ and Schwartz GK: A multicenter phase II study of bortezomib in recurrent or metastatic sarcomas. Cancer. 103:1431–1438. 2005. View Article : Google Scholar : PubMed/NCBI
23	Steinhilb ML, Turner RS and Gaut JR: The protease inhibitor, MG132, blocks maturation of the amyloid precursor protein Swedish mutant preventing cleavage by beta-secretase. J Biol Chem. 276:4476–4484. 2001. View Article : Google Scholar : PubMed/NCBI
24	Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A and Kanthasamy AG: Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology. 27:807–815. 2006. View Article : Google Scholar : PubMed/NCBI
25	Ma Y, Chen B, Liu D, Yang Y, Xiong Z, Zeng J and Dong Y: MG132 treatment attenuates cardiac remodeling and dysfunction following aortic banding in rats via the NF-κB/TGFβ1 pathway. Biochem Pharmacol. 81:1228–1236. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zeng W, Qi W, Mu J, Wei Y, Yang LL, Zhang Q, Wu Q, Tang JY and Feng B: MG132 protects against renal dysfunction by regulating Akt-mediated inflammation in diabetic nephropathy. Sci Rep. 9:20492019. View Article : Google Scholar : PubMed/NCBI
27	Shu Z, Li X, Zhang W, Huyan Z, Cheng D, Xie S, Cheng H, Wang J and Du B: MG-132 activates sodium palmitate-induced autophagy in human vascular smooth muscle cells and inhibits senescence via the PI3K/AKT/mTOR axis. Lipids Health Dis. 23:2822024. View Article : Google Scholar : PubMed/NCBI
28	Gómez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, Gallardo-Nieto J, Lopez-Toledo G, Abarca-Fernandez AM, Zacapala-Gómez AE, Luna-Muñoz J, Montiel-Sosa F, Soto-Rojas LO, et al: Autophagy: A key regulator of homeostasis and disease: An overview of molecular mechanisms and modulators. Cells. 11:22622022. View Article : Google Scholar : PubMed/NCBI
29	Guo C, Sun L, Chen X and Zhang D: Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 8:2003–2014. 2013.PubMed/NCBI
30	Zhitkovich A: N-acetylcysteine: Antioxidant, aldehyde scavenger, and more. Chem Res Toxicol. 32:1318–1319. 2019. View Article : Google Scholar : PubMed/NCBI
31	Anwar S, Alrumaihi F, Sarwar T, Babiker AY, Khan AA, Prabhu SV and Rahmani AH: Exploring therapeutic potential of catalase: Strategies in disease prevention and management. Biomolecules. 14:6972024. View Article : Google Scholar : PubMed/NCBI
32	Mills J, Matos T, Charytonowicz E, Hricik T, Castillo-Martin M, Remotti F, Lee FY and Matushansky I: Characterization and comparison of the properties of sarcoma cell lines in vitro and in vivo. Hum Cell. 22:85–93. 2009. View Article : Google Scholar : PubMed/NCBI
33	Smardová J, Pavlová S, Svitáková M, Grochová D and Ravcuková B: Analysis of p53 status in human cell lines using a functional assay in yeast: Detection of new non-sense p53 mutation in codon 124. Oncol Rep. 14:901–907. 2005.PubMed/NCBI
34	Coley HM, Shotton CF, Kokkinos MI and Thomas H: The effects of the CDK inhibitor seliciclib alone or in combination with cisplatin in human uterine sarcoma cell lines. Gynecol Oncol. 105:462–469. 2007. View Article : Google Scholar : PubMed/NCBI
35	Potts BC, Albitar MX, Anderson KC, Baritaki S, Berkers C, Bonavida B, Chandra J, Chauhan D, Cusack JC Jr, Fenical W, et al: Marizomib, a proteasome inhibitor for all seasons: Preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets. 11:254–284. 2011. View Article : Google Scholar : PubMed/NCBI
36	Alwahsh M, Farhat J, Talhouni S, Hamadneh L and Hergenröder R: Bortezomib advanced mechanisms of action in multiple myeloma, solid and liquid tumors along with its novel therapeutic applications. EXCLI J. 22:146–168. 2023.PubMed/NCBI
37	Latif A, Kapoor V, Lateef N, Ahsan MJ, Usman RM, Malik SU, Ahmad N, Rosko N, Rudoni J, William P, et al: Incidence and management of carfilzomib-induced cardiovascular toxicity; A systematic review and meta-analysis. Cardiovasc Hematol Disord Drug Targets. 21:30–45. 2021. View Article : Google Scholar : PubMed/NCBI
38	Zhai Y, Ye X, Hu F, Xu J, Guo X, Cao Y, Lin Z, Zhou X, Guo Z and He J: Cardiovascular toxicity of carfilzomib: The real-world evidence based on the adverse event reporting system database of the FDA, the United States. Front Cardiovasc Med. 8:7354662021. View Article : Google Scholar : PubMed/NCBI
39	Richardson PG, Zweegman S, O'Donnell EK, Laubach JP, Raje N, Voorhees P, Ferrari RH, Skacel T, Kumar SK and Lonial S: Ixazomib for the treatment of multiple myeloma. Expert Opin Pharmacother. 19:1949–1968. 2018. View Article : Google Scholar : PubMed/NCBI
40	Di K, Lloyd GK, Abraham V, MacLaren A, Burrows FJ, Desjardins A, Trikha M and Bota DA: Marizomib activity as a single agent in malignant gliomas: Ability to cross the blood-brain barrier. Neuro Oncol. 18:840–848. 2016. View Article : Google Scholar : PubMed/NCBI