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CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells

  • Authors:
    • Xuepeng Fu
    • Wen Chen
    • Yang Pan
    • Chang Liu
    • Zhenzhu Zhang
    • Shuli Shao
    • Weiwei Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Life Science and Agroforestry, Qiqihar University, Qiqihar, Heilongjiang 161006, P.R. China
    Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 319
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    Published online on: August 29, 2022
       https://doi.org/10.3892/mmr.2022.12835
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Abstract

Cytidine triphosphate synthase (CTPS) forms filamentous structures termed cytoophidia in numerous types of cell. Toosendanin (TSN) is a tetracyclic triterpenoid and induces CTPS to form cytoophidia in MKN45 cells. However, the effects of CTPS cytoophidia on the proliferation and apoptosis of human gastric cancer cells remain poorly understood. In the present study, CTPS‑overexpression and R294D‑CTPS mutant vectors were generated to assess the effect of CTPS cytoophidia on the proliferation and apoptosis of gastric cancer MKN45 cells. Formation of CTPS cytoophidia significantly inhibited MKN45 cell proliferation (evaluated using EdU incorporation assay), significantly blocked the cell cycle in G1 phase (assessed using flow cytometry) and significantly decreased mRNA and protein expression levels of cyclin D1 (assessed by reverse transcription‑quantitative PCR and western blotting, respectively). Furthermore, the number of apoptotic bodies and apoptosis rate were markedly elevated and mitochondrial membrane potential was markedly decreased. Moreover, mRNA and protein expression levels of Bax increased and Bcl‑2 decreased markedly in MKN45 cells following transfection with the CTPS‑overexpression vector. The proliferation rate increased, percentage of G1/G0‑phase cells decreased and apoptosis was attenuated in cells transfected with the R294D‑CTPS mutant vector and this mutation did not lead to formation of cytoophidia. The results of the present study suggested that formation of CTPS cytoophidia inhibited proliferation and promoted apoptosis in MKN45 cells. These results may provide insights into the role of CTPS cytoophidia in cancer cell proliferation and apoptosis.
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1 

Levitzki A and Koshland DE Jr: Role of an allosteric effector. Guanosine triphosphate activation in cytosine triphosphate synthetase. Biochemistry. 11:241–246. 1972. View Article : Google Scholar : PubMed/NCBI

2 

Liu JL: Intracellular compartmentation of CTP synthase in Drosophila. J Genet Genomics. 37:281–296. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Noree C, Sato BK, Broyer RM and Wilhelm JE: Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster. J Cell Biol. 190:541–551. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Ingerson-Mahar M, Briegel A, Werner JN, Jensen GJ and Gitai Z: The metabolic enzyme CTP synthase forms cytoskeletal filaments. Nat Cell Biol. 12:739–746. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Chang CC, Keppeke GD, Antos CL, Peng M, Andrade LEC, Sung LY and Liu JL: CTPS forms the cytoophidium in zebrafish. Exp Cell Res. 405:1126842021. View Article : Google Scholar : PubMed/NCBI

6 

Carcamo WC, Satoh M, Kasahara H, Terada N, Hamazaki T, Chan JYF, Yao B, Tamayo S, Covini G, von Mühlen CA and Chan EKL: Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells. PLoS One. 6:e296902011. View Article : Google Scholar : PubMed/NCBI

7 

Chen K, Zhang J, Tastan ÖY, Deussen ZA, Siswick MY and Liu JL: Glutamine analogs promote cytoophidium assembly in human and Drosophila cells. J Genet Genomics. 38:391–402. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Aughey GN and Liu JL: Metabolic regulation via enzyme filamentation. Crit Rev Biochem Mol Biol. 51:282–293. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Narvaez-Ortiz HY, Lopez AJ, Gupta N and Zimmermann BH: A CTP synthase undergoing stage-specific spatial expression is essential for the survival of the intracellular parasite toxoplasma gondii. Front Cell Infect Microbiol. 8:832018. View Article : Google Scholar : PubMed/NCBI

10 

Lynch EM, Hicks DR, Shepherd M, Endrizzi JA, Maker A, Hansen JM, Barry RM, Gitai Z, Baldwin EP and Kollman JM: Human CTP synthase filament structure reveals the active enzyme conformation. Nat Struct Mol Biol. 24:507–514. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Wu Z and Liu JL: Cytoophidia respond to nutrient stress in Drosophila. Exp Cell Res. 376:159–167. 2019. View Article : Google Scholar : PubMed/NCBI

12 

Petrovska I, Nüske E, Munder MC, Kulasegaran G, Malinovska L, Kroschwald S, Richter D, Fahmy K, Gibson K, Verbavatz JM and Alberti S: Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation. Elife. 25:e024092014. View Article : Google Scholar

13 

Zhang J and Liu JL: Temperature-sensitive cytoophidium assembly in Schizosaccharomyces pombe. J Genet Genomics. 46:423–432. 2019. View Article : Google Scholar : PubMed/NCBI

14 

Aughey GN, Grice SJ, Shen QJ, Xu Y, Chang CC, Azzam G, Wang PY, Freeman-Mills L, Pai LM, Sung LY, et al: Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism. Biol Open. 3:1045–1056. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Barry RM, Bitbol AF, Lorestani A, Charles EJ, Habrian CH, Hansen JM, Li HJ, Baldwin EP, Wingreen NS, Kollman JM and Gitai Z: Large-scale filament formation inhibits the activity of CTP synthetase. Elife. 16:e036382014. View Article : Google Scholar : PubMed/NCBI

16 

Strochlic TI, Stavrides KP, Thomas SV, Nicolas E, O'Reilly AM and Peterson JR: Ack kinase regulates CTP synthase filaments during Drosophila oogenesis. EMBO Rep. 15:1184–1191. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Kizaki H, Williams JC, Morris HP and Weber G: Increased cytidine 5′-triphosphate synthetase activity in rat and human tumors. Cancer Res. 40:3921–3927. 1980.PubMed/NCBI

18 

Williams JC, Kizaki H, Weber G and Morris HP: Increased CTP synthetase activity in cancer cells. Nature. 271:71–73. 1978. View Article : Google Scholar : PubMed/NCBI

19 

Verschuur AC, Van Gennip AH, Leen R, Meinsma R, Voute PA and van Kuilenburg AB: In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia. Br J Haematol. 110:161–169. 2000. View Article : Google Scholar : PubMed/NCBI

20 

Lin Y, Zhang J, Li Y, Guo W, Chen L, Chen M, Chen X, Zhang W, Jin X, Jiang M, et al: CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1. J Transl Med. 20:172022. View Article : Google Scholar : PubMed/NCBI

21 

Chang CC, Jeng YM, Peng M, Keppeke GD, Sung LY and Liu JL: CTP synthase forms the cytoophidium in human hepatocellular carcinoma. Exp Cell Res. 361:292–299. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Ong ES and Ong CN: Qualitative and quantitative analysis of toosendanin in Melia toosendan Sieb. Et Zucc (Meliaceae) with liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 21:589–598. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Wang G, Feng CC, Chu SJ, Zhang R, Lu YM, Zhu JS and Zhang J: Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway. Int J Oncol. 47:1767–1774. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Zhang C, Gao H, Liu Z, Lai J, Zhan Z, Chen Y and Huang H: Mechanisms involved in the anti-tumor effects of Toosendanin in glioma cells. Cancer Cell Int. 21:4922021. View Article : Google Scholar : PubMed/NCBI

25 

Ruan H, Song Z, Cao Q, Ni D, Xu T, Wang K, Bao L, Tong J, Xiao H, Xiao W, et al: IMPDH1/YB-1 positive feedback loop assembles cytoophidia and represents a therapeutic target in metastatic tumors. Mol Ther. 28:1299–1313. 2020. View Article : Google Scholar : PubMed/NCBI

26 

Shao S, Li S, Liu C, Zhang W, Zhang Z, Zhu S, Feng Y and Pan Y: Toosendanin induces apoptosis of MKN-45 human gastric cancer cells partly through miR-23a-3p-mediated downregulation of BCL2. Mol Med Rep. 22:1793–1802. 2020. View Article : Google Scholar : PubMed/NCBI

27 

Huang Y, Wang JJ, Ghosh S and Liu JL: Critical roles of CTP synthase N-terminal in cytoophidium assembly. Exp Cell Res. 354:122–133. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Wang YM, Wu FJ, Du L, Li GY, Takahashi K, Xue Y and Xue CH: Effects of polysaccharides from abalone (Haliotis discus hannai Ino) on HepG2 cell proliferation. Int J Biol Macromol. 66:354–361. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Sabarwal A, Agarwal R and Singh RP: Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells. Mol Carcinog. 56:499–514. 2017. View Article : Google Scholar : PubMed/NCBI

30 

Zhang W, Tong H, Zhang Z, Shao S, Liu D, Li S and Yan Y: Transcription factor EGR1 promotes differentiation of bovine skeletal muscle satellite cells by regulating MyoG gene expression. J Cell Physiol. 233:350–362. 2018. View Article : Google Scholar : PubMed/NCBI

31 

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 : PubMed/NCBI

32 

Zhang T, Li J, Yin F, Lin B, Wang Z, Xu J, Wang H, Zuo D, Wang G, Hua Y and Cai Z: Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene. 36:6627–6639. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Yang T, Xu R, Huo J, Wang B, Du X, Dai B, Zhu M, Zhan Y, Zhang D and Zhang Y: WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling. Cancer Lett. 513:50–62. 2021. View Article : Google Scholar : PubMed/NCBI

34 

Gao T, Xie A, Liu X, Zhan H, Zeng J, Dai M and Zhang B: Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptotic pathway. Mol Med Rep. 20:135–140. 2019.PubMed/NCBI

35 

Liu JL: The cytoophidium and its kind: Filamentation and compartmentation of metabolic enzymes. Annu Rev Cell Dev Biol. 32:349–372. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Lin WC, Chakraborty A, Huang SC, Wang PY, Hsieh YJ, Chien KY, Lee YH, Chang CC, Tang HY, Lin YT, et al: Histidine-dependent protein methylation is required for compartmentalization of CTP synthase. Cell Rep. 24:2733–2745. 2018. View Article : Google Scholar : PubMed/NCBI

37 

van den Berg AA, van Lenthe H, Kipp JB, de Korte D, van Kuilenburg AB and van Gennip AH: Cytidine triphosphate (CTP) synthetase activity during cell cycle progression in normal and malignant T-lymphocytic cells. Eur J Cancer. 1:108–112. 1995. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Fu X, Chen W, Pan Y, Liu C, Zhang Z, Shao S and Zhang W: CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells. Mol Med Rep 26: 319, 2022.
APA
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., & Zhang, W. (2022). CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells. Molecular Medicine Reports, 26, 319. https://doi.org/10.3892/mmr.2022.12835
MLA
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., Zhang, W."CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells". Molecular Medicine Reports 26.4 (2022): 319.
Chicago
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., Zhang, W."CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells". Molecular Medicine Reports 26, no. 4 (2022): 319. https://doi.org/10.3892/mmr.2022.12835
Copy and paste a formatted citation
x
Spandidos Publications style
Fu X, Chen W, Pan Y, Liu C, Zhang Z, Shao S and Zhang W: CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells. Mol Med Rep 26: 319, 2022.
APA
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., & Zhang, W. (2022). CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells. Molecular Medicine Reports, 26, 319. https://doi.org/10.3892/mmr.2022.12835
MLA
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., Zhang, W."CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells". Molecular Medicine Reports 26.4 (2022): 319.
Chicago
Fu, X., Chen, W., Pan, Y., Liu, C., Zhang, Z., Shao, S., Zhang, W."CTPS cytoophidia formation affects cell cycle progression and promotes TSN‑induced apoptosis of MKN45 cells". Molecular Medicine Reports 26, no. 4 (2022): 319. https://doi.org/10.3892/mmr.2022.12835
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