YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling

Hua Sui; Wanli Deng; Qiong Chai; Bing Han; Yuli Zhang; Zhenzhen Wei; Zan Li; Ting Wang; Jiling Feng; Man Yuan; Qingfeng Tang; Hongxi Xu

doi:10.1016/j.jpha.2023.11.008

Volume 14 Issue 4

Apr. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(4): 100901

Hua Sui, Wanli Deng, Qiong Chai, Bing Han, Yuli Zhang, Zhenzhen Wei, Zan Li, Ting Wang, Jiling Feng, Man Yuan, Qingfeng Tang, Hongxi Xu. YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100901. doi: 10.1016/j.jpha.2023.11.008

Citation:

Hua Sui, Wanli Deng, Qiong Chai, Bing Han, Yuli Zhang, Zhenzhen Wei, Zan Li, Ting Wang, Jiling Feng, Man Yuan, Qingfeng Tang, Hongxi Xu. YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100901. doi: 10.1016/j.jpha.2023.11.008

Citation:

Hua Sui, Wanli Deng, Qiong Chai, Bing Han, Yuli Zhang, Zhenzhen Wei, Zan Li, Ting Wang, Jiling Feng, Man Yuan, Qingfeng Tang, Hongxi Xu. YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling[J]. Journal of Pharmaceutical Analysis, 2024, 14(4): 100901. doi: 10.1016/j.jpha.2023.11.008

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YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling

doi: 10.1016/j.jpha.2023.11.008

Hua Sui^a,b,
Wanli Deng^c,
Qiong Chai^d,
Bing Han^e,
Yuli Zhang^b,
Zhenzhen Wei^a,b,
Zan Li^a,b,
Ting Wang^f,
Jiling Feng^g,
Man Yuan^d,
Qingfeng Tang^{a
,
,},
Hongxi Xu^{b,d
,
,}

a. Medical Experiment Center, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201803, China;
b. Translational Medicine Research Center for Cancer Prevention and Treatment, Shanghai General Hospital Jiading Branch-School of Pharmacy of Shanghai University of Traditional Chinese Medicine Joint Laboratory, Shanghai, 201803, China;
c. Department of Medical Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China;
d. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;
e. The Second Clinical Medical College of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, China;
f. Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;
g. Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

Funds:

This research was supported by “Jiaotong University Star” Program, China (Grant No.: YG2022QN082), the National Natural Science Foundation of China (Grant No.: 82204887), the Science Foundation for Shanghai Committee of Science Project, China (Grant Nos.: 21S21901400 and 23S21901200), and the Natural Science Research Foundation of Jiading District, China (Grant No.: JDKW-2021-0023).

Received Date: May 09, 2023
Accepted Date: Nov. 16, 2023
Rev Recd Date: Nov. 11, 2023
Publish Date: Nov. 29, 2023

Abstract

Abstract

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and in vivo, revealing a significant inhibition of the Wnt family member 5a (Wnt5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing (scRNA-seq) on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of colorectal cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 cell balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.
- Tumor microenvironment,
- Intestinal epithelial cells,
- Treg/Th17 cells,
- Metabolism,
- Wnt5a/JNK signaling,
- Tumorigenesis

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References(50)

References

[1]	L. Zhang, Z. Li, K.M. Skrzypczynska, et al., Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer, Cell 181 (2020) 442-459.e29.
[2]	X. Ma, Z. Meng, L. Jin, et al., CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation, Oncogene 36 (2017) 4060-4071.
[3]	O. Dmitrieva-Posocco, A.C. Wong, P. Lundgren, et al., β-Hydroxybutyrate suppresses colorectal cancer, Nature 605 (2022) 160-165.
[4]	Q. Li, W. Hu, W.-X. Liu, et al., Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting β-galactosidase, Gastroenterology 160 (2021) 1179-1193.e14.
[5]	A. Malik, D. Sharma, R.K.S. Malireddi, et al., SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer, Immunity 49 (2018) 515-530.e5.
[6]	H. Sui, H. Tan, J. Fu, et al., The active fraction of Garcinia yunnanensis suppresses the progression of colorectal carcinoma by interfering with tumorassociated macrophage-associated M2 macrophage polarization in vivo and in vitro, FASEB J. 34 (2020) 7387-7403.
[7]	H. Miyoshi, R. Ajima, C.T. Luo, et al., Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury, Science 338 (2012) 108-113.
[8]	S. Rogers, S. Scholpp, Vertebrate Wnt5a - At the crossroads of cellular signalling, Semin. Cell Dev. Biol. 125 (2022) 3-10.
[9]	K. Wang, F. Ma, S. Arai, et al., WNT5a signaling through ROR2 activates the Hippo pathway to suppress YAP1 activity and tumor growth, Cancer Res. 83 (2023) 1016-1030.
[10]	D. Hasegawa, N. Wada, S. Yoshida, et al., Wnt5a suppresses osteoblastic differentiation of human periodontal ligament stem cell-like cells via Ror2/JNK signaling, J. Cell. Physiol. 233 (2018) 1752-1762.
[11]	D. Bayik, J.D. Lathia, Cancer stem cell-immune cell crosstalk in tumour progression, Nat. Rev. Cancer 21 (2021) 526-536.
[12]	L. Fan, C. Xu, Q. Ge, et al., A. muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-mediated M1-like TAMs, Cancer Immunol. Res. 9 (2021) 1111-1124.
[13]	C.M. Schurch, S.S. Bhate, G.L. Barlow, et al., Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front, Cell 182 (2020) 1341-1359.e19.
[14]	H. Sui, L. Zhang, K. Gu, et al., YYFZBJS ameliorates colorectal cancer progression in ApcMin/+ mice by remodeling gut microbiota and inhibiting regulatory T-cell generation, Cell Commun. Signal. 18 (2020), 113.
[15]	S. Hang, D. Paik, L. Yao, et al., Bile acid metabolites control TH17 and T_reg cell differentiation, Nature 576 (2019) 143-148.
[16]	A. Wagner, C. Wang, J. Fessler, et al., Metabolic modeling of single Th17 cells reveals regulators of autoimmunity, Cell 184 (2021) 4168-4185.e21.
[17]	Y.S. Zhang, D.E. Xin, Z. Wang, et al., STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation, EMBO J. 38 (2019), e99595.
[18]	F. Zhu, H. Li, Y. Liu, et al., miR-155 antagomir protect against DSS-induced colitis in mice through regulating Th17/Treg cell balance by Jarid2/Wnt/β-catenin, Biomed. Pharmacother. 126 (2020), 109909.
[19]	A. Osman, B. Yan, Y. Li, et al., TCF-1 controls T_reg cell functions that regulate inflammation, CD8⁺ T cell cytotoxicity and severity of colon cancer, Nat. Immunol. 22 (2021) 1152-1162.
[20]	R. Kinoshita-Daitoku, K. Kiga, M. Miyakoshi, et al., A bacterial small RNA regulates the adaptation of Helicobacter pylori to the host environment, Nat. Commun. 12 (2021), 2085.
[21]	N. Chai, Y. Xiong, Y. Zhang, et al., YYFZBJS inhibits colorectal tumorigenesis by remodeling gut microbiota and influence on M2 macrophage polarization in vivo and in vitro, Am. J. Cancer Res. 11 (2021) 5338-5357.
[22]	H. Nienhuser, W. Kim, E. Malagola, et al., Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice, Gut 70 (2021) 654-665.
[23]	M. Asem, A.M. Young, C. Oyama, et al., Host Wnt5a potentiates microenvironmental regulation of ovarian cancer metastasis, Cancer Res. 80 (2020) 1156-1170.
[24]	H. Li, X. Meng, L. Zhang, et al., Oblongifolin C and guttiferone K extracted from Garcinia yunnanensis fruit synergistically induce apoptosis in human colorectal cancer cells in vitro, Acta Pharmacol. Sin. 38 (2017) 252-263.
[25]	D.J. Flanagan, N. Pentinmikko, K. Luopajarvi, et al., NOTUM from Apc-mutant cells biases clonal competition to initiate cancer, Nature 594 (2021) 430-435.
[26]	G. Singovski, C. Bernal, M. Kuciak, et al., In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases, J. Mol. Cell Biol. 8 (2016) 157-173.
[27]	Z. Li, L. Mao, B. Yu, et al., GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells, J. Pharm. Anal. 12 (2022) 339-349.
[28]	D.T. Miyamoto, Y. Zheng, B.S. Wittner, et al., RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance, Science 349 (2015) 1351-1356.
[29]	G. Fuertes, B. Del Valle-Perez, J. Pastor, et al., Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation, EMBO Rep. 24 (2023), e54895.
[30]	J. Osman, K. Bellamkonda, Q. Liu, et al., The WNT5A agonist Foxy5 reduces the number of colonic cancer stem cells in a xenograft mouse model of human colonic cancer, Anticancer Res. 39 (2019) 1719-1728.
[31]	X. Wei, J. Gong, J. Ma, et al., Targeting the Dvl-1/β-arrestin2/JNK3 interaction disrupts Wnt5a-JNK3 signaling and protects hippocampal CA1 neurons during cerebral ischemia reperfusion, Neuropharmacology 135 (2018) 11-21.
[32]	J. Zhang, C. Wang, Z. Guo, et al., miR-223 improves intestinal inflammation through inhibiting the IL-6/STAT3 signaling pathway in dextran sodium sulfate-induced experimental colitis, Immun. Inflamm. Dis. 9 (2021) 319-327.
[33]	T.-W. Kim, J.-S. Shin, K.-S. Chung, et al., Anti-inflammatory mechanisms of koreanaside A, a lignan isolated from the flower of Forsythia koreana, against LPS-induced macrophage activation and DSS-induced colitis mice: The crucial role of AP-1, NF-κB, and JAK/STAT signaling, Cells 8 (2019), 1163.
[34]	L. Dong, J. Xie, Y. Wang, et al., Mannose ameliorates experimental colitis by protecting intestinal barrier integrity. Nat. Commun. 13 (2022), 4804.
[35]	M. Lleal, G. Sarrabayrouse, J. Willamil, et al., A single faecal microbiota transplantation modulates the microbiome and improves clinical manifestations in a rat model of colitis, EBioMedicine 48 (2019) 630-641.
[36]	H. Tilg, T.E. Adolph, R.R. Gerner, et al., The intestinal microbiota in colorectal cancer, Cancer Cell 33 (2018) 954-964.
[37]	J. Roelands, M. van der Ploeg, M.E. Ijsselsteijn, et al., Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis, Gut 72 (2023) 1326-1339.
[38]	E. Loeuillard, J. Yang, E. Buckarma, et al., Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma, J. Clin. Invest. 130 (2020) 5380-5396.
[39]	Y. Lu, Y. Li, Q. Liu, et al., MondoA-thioredoxin-interacting protein axis maintains regulatory T-cell identity and function in colorectal cancer microenvironment, Gastroenterology 161 (2021) 575-591.e16.
[40]	T. Poutahidis, V.P. Rao, W. Olipitz, et al., CD4⁺ lymphocytes modulate prostate cancer progression in mice, Int. J. Cancer 125(2009) 868-878.
[41]	Y.L. Phang, C. Zheng, H. Xu, Structural diversity and biological activities of caged Garcinia xanthones: Recent updates, Acta Mater. Med. 1 (2022) 72-95.
[42]	Y. Zhang, L. Huo, Z. Wei, et al., Hotspots and frontiers in inflammatory tumor microenvironment research: A scientometric and visualization analysis, Front. Pharmacol. 13 (2022), 862585.
[43]	Y. Zhang, N. Chai, Z. Wei, et al., YYFZBJS inhibits colorectal tumorigenesis by enhancing Tregs-induced immunosuppression through HIF-1α mediated hypoxia in vivo and in vitro, Phytomedicine 98 (2022), 153917.
[44]	X. Bai, R. Fu, Y. Liu, et al., Ginsenoside Rk3 modulates gut microbiota and regulates immune response of group 3 innate lymphoid cells to against colorectal tumorigenesis. J. Pharm. Anal. 14 (2024) 259-275.
[45]	B. Xin, M. Yang, P. Wu, et al., Enhancing the therapeutic efficacy of programmed death ligand 1 antibody for metastasized liver cancer by overcoming hepatic immunotolerance in mice, Hepatology 76 (2022) 630-645.
[46]	J. Zhou, X. Li, X. Wu, et al., Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer, Cancer Immunol. Res. 6 (2018) 1578-1592.
[47]	A.I. Robles, G. Traverso, M. Zhang, et al., Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers, Gastroenterology 150 (2016) 931-943.
[48]	J. Quandt, S. Arnovitz, L. Haghi, et al., Wnt-β-catenin activation epigenetically reprograms T_reg cells in inflammatory bowel disease and dysplastic progression, Nat. Immunol. 22 (2021) 471-484.
[49]	M. Pashirzad, T. Sathyapalan, A. Sahebkar, Clinical importance of Wnt5a in the pathogenesis of colorectal cancer, J. Oncol. 2021 (2021), 3136508.
[50]	Q. Liu, C. Yang, S. Wang, et al., Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression, Cell Commun. Signal. 18 (2020), 51.