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Apoptosis of Kinetin Riboside in Colorectal Cancer Cells Occurs by Promoting β-Catenin Degradation

  • TaeKyung Nam (Department of Bio and Fermentation Convergence Technology, Kookmin University) ;
  • Wonku Kang (College of Pharmacy, Chung-Ang University) ;
  • Sangtaek Oh (Department of Bio and Fermentation Convergence Technology, Kookmin University)
  • Received : 2023.01.28
  • Accepted : 2023.05.23
  • Published : 2023.09.28

Abstract

The Wnt/β-catenin pathway plays essential roles in regulating various cellular behaviors, including proliferation, survival, and differentiation [1-3]. The intracellular β-catenin level, which is regulated by a proteasomal degradation pathway, is critical to Wnt/β-catenin pathway control [4]. Normally, casein kinase 1 (CK1) and glycogen synthase kinase-3β (GSK-3β), which form a complex with the scaffolding protein Axin and the tumor suppressor protein adenomatous polyposis coli (APC), phosphorylate β-catenin at Ser45, Thr41, Ser37, and Ser33 [5, 6]. Phosphorylated β-catenin is ubiquitinated by the β-transducin repeat-containing protein (β-TrCP), an F-box E3 ubiquitin ligase complex, and ubiquitinated β-catenin is degraded via a proteasome pathway [7, 8]. Colorectal cancer is a significant cause of cancer-related deaths worldwide. Abnormal up-regulation of the Wnt/β-catenin pathway is a major pathological event in intestinal epithelial cells during human colorectal cancer oncogenesis [9]. Genetic mutations in the APC gene are observed in familial adenomatous polyposis coli (FAP) and sporadic colorectal cancers [10]. In addition, mutations in the N-terminal phosphorylation motif of the β-catenin gene were found in patients with colorectal cancer [11]. These mutations cause β-catenin to accumulate in the nucleus, where it forms complexes with transcription factors of the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family to stimulate the expression of β-catenin responsive genes, such as c-Myc and cyclin D1, which leads to colorectal tumorigenesis [12-14]. Therefore, downregulating β-catenin response transcription (CRT) is a potential strategy for preventing and treating colorectal cancer. Plant cytokinins are N6-substituted purine derivatives; they promote cell division in plants and regulate developmental pathways. Natural cytokinins are classified as isoprenoid (isopentenyladenine, zeatin, and dihydrozeatin), aromatic (benzyladenine, topolin, and methoxytopolin), or furfural (kinetin and kinetin riboside), depending on their structure [15, 16]. Kinetin riboside was identified in coconut water and is a naturally produced cytokinin that induces apoptosis and exhibits antiproliferative activity in several human cancer cell lines [17]. However, little attention has been paid to kinetin riboside's mode of action. In this study, we show that kinetin riboside exerts its cytotoxic activity against colon cancer cells by suppressing the Wnt/β-catenin pathway and promoting intracellular β-catenin degradation.

Keywords

Acknowledgement

This work was supported by the Fundamental Technology Program (2020R1A2C1010109) through the National Research Foundation of Korea (NRF) funded by the Korean Government and by Korea Environmental Industry and Technology Institute (KEITI) grant funded by the Ministry of Environment of Korea.

References

  1. Wodarz A, Nusse R. 1998. Mechanisms of Wnt signaling in development. Annu. Rev. Cell Dev. Biol. 14: 59-88. https://doi.org/10.1146/annurev.cellbio.14.1.59
  2. Huelsken J, Birchmeier W. 2001. New aspects of Wnt signaling pathways in higher vertebrates. Curr. Opin. Genet. Dev. 11: 547-553. https://doi.org/10.1016/S0959-437X(00)00231-8
  3. Miller JR. 2001. The wnts. Genome Biology 3: 1-15. https://doi.org/10.1186/gb-2001-3-1-reviews3001
  4. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. 2002. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108: 837-847. https://doi.org/10.1016/S0092-8674(02)00685-2
  5. Hart MJ, De Los Santos R, Albert IN, Rubinfeld B, Polakis P. 1998. Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8: 573-581. https://doi.org/10.1016/S0960-9822(98)70226-X
  6. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. 1998. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J. 17: 1371-1384. https://doi.org/10.1093/emboj/17.5.1371
  7. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. 1997. β-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16: 3797-3804. https://doi.org/10.1093/emboj/16.13.3797
  8. Hart M, Concordet J, Lassot I, Albert I, Del los Santos R, Durand H, et al. 1999. The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Curr. Biol. 9: 207-211. https://doi.org/10.1016/S0960-9822(99)80091-8
  9. Giles RH, Van Es JH, Clevers H. 2003. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim. Biophys. Acta 1653: 1-24. https://doi.org/10.1016/S0304-419X(03)00005-2
  10. Fearnhead NS, Britton MP, Bodmer WF. 2001. The ABC of APC. Hum. Mol. Genet. 10: 721-733. https://doi.org/10.1093/hmg/10.7.721
  11. Morin PJ. 1999. β-catenin signaling and cancer. Bioessays 21: 1021-1030. https://doi.org/10.1002/(SICI)1521-1878(199912)22:1<1021::AID-BIES6>3.0.CO;2-P
  12. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, Da Costa LT, et al. 1998. Identification of c-MYC as a target of the APC pathway. Science 281: 1509-1512. https://doi.org/10.1126/science.281.5382.1509
  13. He TC, Chan TA, Vogelstein B, Kinzler KW. 1999. PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99: 335-345. https://doi.org/10.1016/S0092-8674(00)81664-5
  14. Tetsu O, McCormick F. 1999. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422-426. https://doi.org/10.1038/18884
  15. Barciszewski J, Massino F, Clark BF. 2007. Kinetin-a multiactive molecule. Int. J. Biol. Macromol. 40: 182-192. https://doi.org/10.1016/j.ijbiomac.2006.06.024
  16. Griffaut B, Bos R, Maurizis JC, Madelmont JC, Ledoigt G. 2004. Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells. Int. J. Biol. Macromol. 34: 271-275. https://doi.org/10.1016/j.ijbiomac.2004.06.004
  17. Ge L, Yong JWH, Goh NK, Chia LS, Tan SN, Ong ES. 2005. Identification of kinetin and kinetin riboside in coconut (Cocos nucifera L.) water using a combined approach of liquid chromatography-tandem mass spectrometry, high performance liquid chromatography and capillary electrophoresis. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 829: 26-34. https://doi.org/10.1016/j.jchromb.2005.09.026
  18. Shen M, Hu Y, Yang Y, Wang L, Yang X, Wang B, et al. 2019. Betulinic acid induces ROS-dependent apoptosis and S-phase arrest by inhibiting the NF-κB pathway in human multiple myeloma. Oxid. Med. Cell. Longev. 2019: 5083158.
  19. Dignam JD, Lebovitz RM, Roeder RG. 1983. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11: 1475-1489. https://doi.org/10.1093/nar/11.5.1475
  20. Park S, Gwak J, Cho M, Song T, Won J, Kim DE, et al. 2006. Hexachlorophene inhibits Wnt/β-catenin pathway by promoting Siahmediated β-catenin degradation. Mol. Pharmacol. 70: 960-966. https://doi.org/10.1124/mol.106.024729
  21. Meijer L, Skaltsounis A-L, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, et al. 2003. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem. Biol. 10: 1255-1266. https://doi.org/10.1016/j.chembiol.2003.11.010
  22. Ilyas M, Tomlinson I, Rowan A, Pignatelli M, Bodmer W. 1997. β-Catenin mutations in cell lines established from human colorectal cancers. Proc. Natil. Acad. Sci. USA 94: 10330-10334. https://doi.org/10.1073/pnas.94.19.10330
  23. Roh H, Green DW, Boswell CB, Pippin JA, Drebin JA. 2001. Suppression of β-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells. Cancer Res. 61: 6563-6568.
  24. Barker N, Clevers H. 2000. Catenins, Wnt signaling and cancer. Bioessays 22: 961-965. https://doi.org/10.1002/1521-1878(200011)22:11<961::AID-BIES1>3.0.CO;2-T
  25. Cabello CM, Bair III WB, Ley S, Lamore SD, Azimian S, Wondrak GT. 2009. The experimental chemotherapeutic N6-furfuryladenosine (kinetin-riboside) induces rapid ATP depletion, genotoxic stress, and CDKN1A (p21) upregulation in human cancer cell lines. Biochem. Pharmacol. 77: 1125-1138. https://doi.org/10.1016/j.bcp.2008.12.002
  26. Rajabi M, Gorincioi E, Santaniello E. 2012. Antiproliferative activity of kinetin riboside on HCT-15 colon cancer cell line. Nucleosides, Nucleotides Nucleic Acids 31: 474-481. https://doi.org/10.1080/15257770.2012.681825
  27. Gwak J, Lee JH, Chung YH, Song GY, Oh S. 2012. Small molecule-based promotion of PKCα-mediated β-catenin degradation suppresses the proliferation of CRT-positive cancer cells. PLoS One 7: e46697.
  28. Zhang Y, Chen H. 2011. Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Exp. Biol. Med. 236: 714-722. https://doi.org/10.1258/ebm.2011.010347
  29. Chen HJ, Hsu LS, Shia YT, Lin MW, Lin CM. 2012. The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway. Biochem. Pharmacol. 84: 1143-1153. https://doi.org/10.1016/j.bcp.2012.08.011
  30. Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, et al. 2008. Natural derivatives of curcumin attenuate the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem. Biophys. Res. Commun. 377: 1304-1308. https://doi.org/10.1016/j.bbrc.2008.10.171
  31. Park CH, Chang JY, Hahm ER, Park S, Kim HK, Yang CH. 2005. Quercetin, a potent inhibitor against β-catenin/Tcf signaling in SW480 colon cancer cells. Biochem. Biophys. Res. Commun. 328: 227-234. https://doi.org/10.1016/j.bbrc.2004.12.151