DOI QR코드

DOI QR Code

Anti-proliferative Efficacy of Xanthorrhizol on Cancer Cells via Activation of hTAS2R38 among 25 Human Bitter Taste Receptors

  • 투고 : 2024.04.02
  • 심사 : 2024.06.30
  • 발행 : 2024.06.30

초록

Human bitter taste-sensing type 2 receptors (hTAS2Rs) are expressed in various human tissues and may be associated with various cell signaling pathways, cell progression, and cell physiology in each tissue. hTAS2Rs can be a potential drug target because it is also expressed in some cancer cells. Xanthorrhizol (XNT) has various biological activities, such as anticancer, antimicrobial, anti-inflammatory, and antioxidant. XNT produces a bitter taste, but the specific hTAS2R activated is unknown, and the hTAS2R-mediated effect of XNT on cancer cells has not been studied. This study discovered the target receptor of XNT among 25 hTAS2Rs and confirmed the possibility of the hTAS2R-mediated inhibition of cancer cell proliferation. XNT activated only one receptor, hTAS2R38 (EC50=1.606±0.021 ㎍/mL), and its activity was inhibited by probenecid, a hTAS2R38 antagonist. When HepG2 and MCF-7 cells were treated with XNT or phenylthiocarbamide (PTC), a known hTAS2R38 agonist, both chemicals inhibited cancer cell proliferation. XNT targets the human bitter taste receptor TAS2R38 and inhibits the proliferation of HepG2 and MCF-7 cells mediated by TAS2R38. This suggests that TAS2R38 may be a new target for disease treatment and a potential new factor for drug development.

키워드

과제정보

This research is supported by Main Research Program (E0232201) of the Korea Food Research Institute.

참고문헌

  1. Ahmad R, Dalziel JE. 2020. G Protein-Coupled Receptors in Taste Physiology and Pharmacology. Front Pharmacol., 11:587664
  2. Ammon C, Schafer J, Kreuzer OJ, Meyerhof W. 2002. Presence of a plasma membrane targeting sequence in the amino-terminal region of the rat somatostatin receptor 3. Arch. Physiol. Biochem., 110(1-2):137-145 https://doi.org/10.1076/apab.110.1.137.908
  3. Andres-Barquin PJ, Conte C. 2004. Molecular basis of bitter taste: the T2R family of G protein-coupled receptors. Cell Biochem. Biophys., 41(1):99-112 https://doi.org/10.1385/CBB:41:1:099
  4. Bhalodia NR, Shukla VJ. 2011. Antibacterial and antifungal activities from leaf extracts of Cassia fistula l.: An ethnomedicinal plant. J. Adv. Pharm. Technol. Res., 2(2):104-109 https://doi.org/10.4103/2231-4040.82956
  5. Breslin PA. 2013. An evolutionary perspective on food and human taste. Curr. Biol., 23(9):R409-418 https://doi.org/10.1016/j.cub.2013.04.010
  6. Carey RM, Lee RJ. 2019. Taste Receptors in Upper Airway Innate Immunity. Nutrients, 11(9):2017
  7. Cheah YH, Azimahtol HL, Abdullah NR. 2006. Xanthorrhizol exhibits antiproliferative activity on MCF-7 breast cancer cells via apoptosis induction. Anticancer Res., 26(6B):4527-4534
  8. Choi JH, Lee J, Choi IJ, Kim YW, Ryu KW, Kim J. 2016. Genetic Variation in the TAS2R38 Bitter Taste Receptor and Gastric Cancer Risk in Koreans. Sci. Rep., 6:26904
  9. Chung WY, Park JH, Kim MJ, Kim HO, Hwang JK, Lee SK, Park KK. 2007. Xanthorrhizol inhibits 12-O-tetra-decanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-kappa B. Carcinogenesis, 28(6):1224-1231 https://doi.org/10.1093/carcin/bgm005
  10. Costa AR, Duarte AC, Costa-Brito AR, Goncalves I, Santos CRA. 2023. Bitter taste signaling in cancer. Life Sci., 315:121363
  11. Foster SR, Porrello ER, Purdue B, Chan HW, Voigt A, Frenzel S, Hannan RD, Moritz KM, Simmons DG, Molenaar P, Roura E, Boehm U, Meyerhof W, Thomas WG. 2013. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart. PLoS One, 8(5):e64579
  12. Gaida MM, Mayer C, Dapunt U, Stegmaier S, Schirmacher P, Wabnitz GH, Hansch GM. 2016. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget, 7(11):12623-12632 https://doi.org/10.18632/oncotarget.7206
  13. Gopallawa I, Freund JR, Lee RJ. 2021. Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling. Cell Mol. Life Sci.,78(1):271-286
  14. Grassin-Delyle S, Abrial C, Fayad-Kobeissi S, Brollo M, Faisy C, Alvarez JC, Naline E, Devillier P. 2013. The expression and relaxant effect of bitter taste receptors in human bronchi. Respir. Res., 14(1):134
  15. Handayani T, Sakinah S, Nallappan M, Pihie AH. 2007. Regulation of p53-, Bcl-2- and caspase-dependent signaling pathway in xanthorrhizol-induced apoptosis of HepG2 hepatoma cells. Anticancer Res., 27(2):965-971
  16. Ismail N, Pihie AH, Nallapan M. 2005. Xanthorrhizol induces apoptosis via the upregulation of bax and p53 in HeLa cells. Anticancer Res., 25(3B):2221-2227
  17. Janssen S, Depoortere I. 2013. Nutrient sensing in the gut: new roads to therapeutics? Trends Endocrinol. Metab., 24(2):92-100 https://doi.org/10.1016/j.tem.2012.11.006
  18. Kim MB, Kim C, Song Y, Hwang JK. 2014. Antihyperglycemic and Anti-Inflammatory Effects of Standardized Curcuma xanthorrhiza Roxb. Extract and Its Active Compound Xanthorrhizol in High-Fat Diet-Induced Obese Mice. Evid. Based Complement Alternat. Med., 2014:205915
  19. Li F, Zhou M. 2012. Depletion of bitter taste transduction leads to massive spermatid loss in transgenic mice. Mol. Hum. Reprod., 18(6):289-297 https://doi.org/10.1093/molehr/gas005
  20. Lu P, Zhang CH, Lifshitz LM, ZhuGe R. 2017. Extraoral bitter taste receptors in health and disease. J. Gen. Physiol., 149(2):181-197 https://doi.org/10.1085/jgp.201611637
  21. Martin LTP, Nachtigal MW, Selman T, Nguyen E, Salsman J, Dellaire G, Dupre DJ. 2019. Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival. Mol. Cell. Biochem., 454(1-2):203-214 https://doi.org/10.1007/s11010-018-3464-z
  22. Maurer S, Wabnitz GH, Kahle NA, Stegmaier S, Prior B, Giese T, Gaida MM, Samstag Y, Hansch GM. 2015. Tasting Pseudomonas aeruginosa Biofilms: Human Neutrophils Express the Bitter Receptor T2R38 as Sensor for the Quorum Sensing Molecule N-(3-Oxododecanoyl)-l-Homoserine Lactone. Front Immunol., 6:369
  23. Nariya PB, Bhalodia NR, Shukla VJ, Acharya RN. 2011. Antimicrobial and antifungal activities of Cordia dichotoma (Forster F.) bark extracts. Ayu., 32(4):585-589 https://doi.org/10.4103/0974-8520.96138
  24. Oon SF, Nallappan M, Tee TT, Shohaimi S, Kassim NK, Sa'ariwijaya MS, Cheah YH. 2015. Xanthorrhizol: a review of its pharmacological activities and anticancer properties. Cancer Cell Int., 15:100
  25. Rukayadi Y, Yong D, Hwang JK. 2006. In vitro anticandidal activity of xanthorrhizol isolated from Curcuma xanthorrhiza Roxb. J. Antimicrob. Chemother., 57(6):1231-1234 https://doi.org/10.1093/jac/dkl132
  26. Saleem M, Afaq F, Adhami VM, Mukhtar H. 2004. Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene, 23(30):5203-5214 https://doi.org/10.1038/sj.onc.1207641
  27. Singh N, Chakraborty R, Bhullar RP, Chelikani P. 2014. Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells. Biochem. Biophys. Res. Commun., 446(2):499-503 https://doi.org/10.1016/j.bbrc.2014.02.140
  28. Tuzim K, Korolczuk A. 2021. An update on extra-oral bitter taste receptors. J. Transl. Med. 19(1):440
  29. Ueda T, Ugawa S, Yamamura H, Imaizumi Y, Shimada S. 2003. Functional interaction between T2R taste receptors and G-protein alpha subunits expressed in taste receptor cells. J. Neurosci. 23(19):7376-7380 https://doi.org/10.1523/JNEUROSCI.23-19-07376.2003
  30. Upadhyaya JD, Singh N, Sikarwar AS, Chakraborty R, Pydi SP, Bhullar RP, Dakshinamurti S, Chelikani P. 2014. Dextromethorphan mediated bitter taste receptor activation in the pulmonary circuit causes vasoconstriction. PLoS One, 9(10):e110373
  31. Wolfle U, Elsholz FA, Kersten A, Haarhaus B, Muller WE, Schempp CM. 2015. Expression and functional activity of the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes. Skin Pharmacol. Physiol., 28(3):137-146 https://doi.org/10.1159/000367631
  32. Wu SV, Rozengurt N, Yang M, Young SH, Sinnett-Smith J, Rozengurt E. 2002. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proc. Natl. Acad. Sci. U S A., 99(4):2392-2397 https://doi.org/10.1073/pnas.042617699
  33. Zehentner S, Reiner AT, Grimm C, Somoza V. 2021. The Role of Bitter Taste Receptors in Cancer: A Systematic Review. Cancers (Basel), 13(23):5891