| Citation: | Caiyi Yang, Kehan Chen, Yunliang Chen, Xuting Xie, Pengcheng Li, Meng Zhao, Junjie Liang, Xueqian Xie, Xiaoyun Chen, Yanping Cai, Bo Xu, Qing Wang, Lian Zhou, Xia Luo. Liquiritin improves macrophage degradation of engulfed tumour cells by promoting the formation of phagolysosomes via NOX2/gp91phox[J]. Journal of Pharmaceutical Analysis, 2025, 15(5): 101093. doi: 10.1016/j.jpha.2024.101093
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The incomplete degradation of tumour cells by macrophages (Mϕ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mϕ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mϕ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mϕ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mϕ phagosomes, causing Mϕ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mϕ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mϕ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mϕ to degrade tumour cells by suppressing NOX2.
| [1] |
L. Cassetta, J.W. Pollard, Tumour-associated macrophages, Curr. Biol. 30 (2020) R246-R248.
|
| [2] |
Y. Pan, Y. Yu, X. Wang, et al., Tumour-associated macrophages in tumour immunity, Front. Immunol. 11 (2020), 583084.
|
| [3] |
H. Wang, T. Tian, J. Zhang, Tumour-associated macrophages (TAMs) in colorectal cancer (CRC): From mechanism to therapy and prognosis, Int. J. Mol. Sci. 22 (2021), 8470.
|
| [4] |
Y. Qiu, T. Chen, R. Hu, et al., Next frontier in tumour immunotherapy: Macrophage-mediated immune evasion, Biomark. Res. 9 (2021), 72.
|
| [5] |
M. Feng, W. Jiang, B.Y.S. Kim, et al., Phagocytosis checkpoints as new targets for cancer immunotherapy, Nat. Rev. Cancer 19 (2019) 568-586.
|
| [6] |
S.M. Kelley, K.S. Ravichandran, Putting the brakes on phagocytosis: "don't-eat-me" signaling in physiology and disease, EMBO. Rep. 22 (2021), e52564.
|
| [7] |
M.A. Morrissey, N. Kern N, R.D. Vale, CD47 ligation repositions the inhibitory receptor SIRPA to suppress integrin activation and phagocytosis, Immunity. 53 (2020) 290-302.
|
| [8] |
Y. Xi, L. Chen, J. Tang, et al., Amplifying "eat me signal" by immunogenic cell death for potentiating cancer immunotherapy, Immunol. Rev. 321 (2024) 94-114.
|
| [9] |
T.O.J. Cockram, J.M. Dundee, A.S. Popescu, et al., The phagocytic code regulating phagocytosis of mammalian cells, Front. Immunol. 12 (2021), 629979.
|
| [10] |
S. Paget, The distribution of secondary growths in cancer of the breast, Cancer. Metastasis. Rev. 8 (1989) 98-101.
|
| [11] |
T.N. Seyfried, L.C. Huysentruyt, On the origin of cancer metastasis, Crit. Rev. Oncog. 18 (2013) 43-73.
|
| [12] |
H. Wang, M.M.H. Yung, H.Y.S. Ngan, et al., The impact of the tumour microenvironment on macrophage polarization in cancer metastatic progression, Int. J. Mol. Sci. 22 (2021), 6560.
|
| [13] |
M. Akhtar, A. Haider, S. Rashid, et al., Paget's "seed and soil" theory of cancer metastasis: An idea whose time has come, Adv. Anat. Pathol. 26 (2019) 69-74.
|
| [14] |
C.E. Gast, A.D. Silk, L. Zarour, et al., Cell fusion potentiates tumour heterogeneity and reveals circulating hybrid cells that correlate with stage and survival, Sci. Adv. 4 (2018), eaat7828.
|
| [15] |
Y. Manjunath, D. Porciani, J.B. Mitchem, et al., Tumour-cell-macrophage fusion cells as liquid biomarkers and tumour enhancers in cancer, Int. J. Mol. Sci. 21 (2020), 1872.
|
| [16] |
M. Kloc, A. Subuddhi, A. Uosef, et al., Monocyte-macrophage lineage cell fusion, Int. J. Mol. Sci. 23 (2022), 6553.
|
| [17] |
T.L. Sutton, R.K. Patel, A.N. Anderson, et al., Circulating cells with macrophage-like characteristics in cancer: The importance of circulating neoplastic-immune hybrid cells in cancer, Cancers. 14 (2022), 3871.
|
| [18] |
V. Riazanski, Z. Sui, D.J. Nelson, Kinetic separation of oxidative and non-oxidative metabolism in single phagosomes from alveolar macrophages: Impact on bacterial killing, iScience. 23 (2020), 101759.
|
| [19] |
H. Grauers Wiktorin, E. Aydin, K. Hellstrand, et al., NOX2-derived reactive oxygen species in cancer, Oxid. Med. Cell. Longev. 2020 (2020), 7095902.
|
| [20] |
C.L. Kuo, A. Ponneri Babuharisankar, Y.C. Lin, et al., Mitochondrial oxidative stress in the tumour microenvironment and cancer immunoescape: Foe or friend?, J. Biomed. Sci. 29 (2022), 74.
|
| [21] |
J. Wang, N. Liu N, H. Jiang, et al., Reactive oxygen species in anticancer immunity: A double-edged sword, Front. Bioeng. Biotechnol. 9 (2021), 784612.
|
| [22] |
J. Wang, Y. Zhou, Y. Cui, et al., Research progress on material basis and mechanism of Glycyrrhizae Radix et Rhizoma enhancing immunity, Chin. Tradit. Herb. Drugs. 52 (2021) 1844-1850.
|
| [23] |
Y. Cong, R. Mijiti, P. Abulizi, et al., Effects of polysaccharide from Glycyrrhiza Inflata on immune function of RAW264.7 macrophage cell line, Chin. Archiv. Traditional Chin. Med. 36 (2018) 1043-1047.
|
| [24] |
Y. Yang, X. Lu, P. Song, et al., Correlation analysis between HPLC fingerprint and antioxidant activity of Glycyrrhizae Radix et Rhizoma, Chin. J. Pharm. Anal. 42 (2022) 607-617.
|
| [25] |
L. He, H. Pei, J. Zeng, et al., Optimization of extraction technology of flavonoids from stem and leaf of Glycyrrhiza and study on antioxidant damag], 2022. https://doi.org/10.13327/j.jjlau.2021.1561.
|
| [26] |
Z. Pan, X. Xie, Y. Chen, et al., Huang Qin Decoction inhibits the initiation of experimental colitis associated carcinogenesis by controlling the PAD4 dependent NETs, Phytomedicine. 107 (2022), 154454.
|
| [27] |
A. Savina, P. Vargas, P. Guermonprez, et al, ROS production, maturation, and degradation in dendritic cell phagosomes using cytofluorometry-based assays, Methods Mol. Biol. 595 (2010) 383-402.
|
| [28] |
L.M. Smith, R.C. May, Mechanisms of microbial escape from phagocyte killing, Biochem. Soc. Trans. 41 (2013), 475-490.
|
| [29] |
C. Leseigneur, P. Le-Bury, J. Pizarro-Cerda, et al., Emerging evasion mechanisms of macrophage defenses by pathogenic bacteria, Front. Cell. Infect. Microbiol. 10 (2020), 577559.
|
| [30] |
E.C. Padilha, P. Shah, G. Rai G, et al., NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization, J. Pharm. Biomed. Anal. 201 (2021), 114102.
|
| [31] |
K. Hirano, W.S. Chen, A.L. Chueng, et al., Discovery of GSK2795039, a novel small molecule NADPH Oxidase 2 inhibitor, Antioxidants Redox Signal. 23 (2015) 358-374.
|
| [32] |
G. Pastorino, L. Cornara, S. Soares, et al., Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review, Phytother Res. 32 (2018) 2323-2339.
|
| [33] |
X. Lian, Y. Ling, S. Zhang, et al., Anti-tumour mechanism of active ingredients of Glycyrrhizae Radix et Rhizomaand and its combined use in anti-tumour treatment: a review, Chin. J. Exp. Tradit. Med. Formulae. 28 (2022) 238-245.
|
| [34] |
S. Jiang, Preliminary Study of Licorice Blending Medicines from the Perspective of Immunology [master's Thesis], Anhui: Anhui University of Chinese Medicine, 2021.
|
| [35] |
Z. Li, E. Hao, H. Li, et al., Pharmacological effect of Glycyrrizae Radix et Rhizoma compatibility and its mechanism, Chin. J. Exp. Tradit. Med. Formulae. 28 (2022) 270-282.
|
| [36] |
M. Lecoultre, V. Dutoit, P.R. Walker, Phagocytic function of tumour-associated macrophages as a key determinant of tumour progression control: A review, J. Immunother. Cancer. 8 (2020), e001408.
|
| [37] |
E.M. Muntjewerff, L.D. Meesters, G. van den Bogaart, Antigen cross-presentation by macrophages, Front. Immunol. 11 (2020), 1276.
|
| [38] |
J.L. Guerriero, Macrophages: Their untold story in T cell activation and function, Int. Rev. Cell. Mol. Biol. 342 (2019) 73-93.
|
| [39] |
W.M. Nauseef, The phagocyte NOX2 NADPH oxidase in microbial killing and cell signalling, Curr. Opin. Immunol. 60 (2019) 130-140.
|
| [40] |
L. Piacenza, M. Trujillo, R. Radi, Reactive species and pathogen antioxidant networks during phagocytosis, J. Exp. Med. 216 (2019) 501-516.
|
| [41] |
K. Bode, M. Hauri-Hohl, V. Jaquet, et al., Unlocking the power of NOX2: A comprehensive review on its role in immune regulation, Redox Biol. 64 (2023), 102795.
|
| [42] |
Z.M. Moghadam, P. Henneke, J. Kolter, From flies to men: ROS and the NADPH oxidase in phagocytes, Front. Cell Dev. Biol. 9 (2021), 628991.
|
| [43] |
M.H. Paclet, S. Laurans, S. Dupre-Crochet, Regulation of neutrophil NADPH oxidase, NOX2: A crucial effector in neutrophil phenotype and function, Front. Cell Dev. Biol. 10 (2022), 945749.
|
| [44] |
S. Noreng, N. Ota, Y. Sun Y, et al., Structure of the core human NADPH oxidase NOX2, Nat. Commun. 13 (2022), 6079.
|
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