The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Jul 12

PMID 34248973

Citations 11

Authors

Takashi Maruyama

Shuhei Kobayashi

Hiroko Nakatsukasa

Yuki Moritoki

Daiki Taguchi

Yoichi Sunagawa

Tatsuya Morimoto

Atsuko Asao

Wenwen Jin

Yuji Owada

Naoto Ishii

Yoshiharu Iwabuchi

Akihiko Yoshimura

Wanjun Chen

Hiroyuki Shibata

Affiliations

Soon will be listed here.

Abstract

Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3 Tregs from naïve CD4 T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the locus and induces gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β. tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3 Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.

Citing Articles

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References

Ohori H, Yamakoshi H, Tomizawa M, Shibuya M, Kakudo Y, Takahashi A . Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol Cancer Ther. 2006; 5(10):2563-71. DOI: 10.1158/1535-7163.MCT-06-0174. View

Hossain D, Panda A, Chakrabarty S, Bhattacharjee P, Kajal K, Mohanty S . MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu. Immunology. 2014; 144(4):561-73. PMC: 4368163. DOI: 10.1111/imm.12397. View

Maruyama T . Memorial: Tatsushi Muta, 1963-2013. J Leukoc Biol. 2015; 98(3):295. DOI: 10.1189/jlb.2LT0515-222. View

Uehara Y, Inoue M, Fukuda K, Yamakoshi H, Hosoi Y, Kanda H . Inhibition of β-catenin and STAT3 with a curcumin analog suppresses gastric carcinogenesis in vivo. Gastric Cancer. 2014; 18(4):774-83. PMC: 4572076. DOI: 10.1007/s10120-014-0434-3. View

Rubtsov Y, Rudensky A . TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 2007; 7(6):443-53. DOI: 10.1038/nri2095. View

Egen J, Ouyang W, Wu L . Human Anti-tumor Immunity: Insights from Immunotherapy Clinical Trials. Immunity. 2020; 52(1):36-54. DOI: 10.1016/j.immuni.2019.12.010. View

Hutzen B, Friedman L, Sobo M, Lin L, Cen L, De Angelis S . Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas. Int J Oncol. 2009; 35(4):867-72. DOI: 10.3892/ijo_00000401. View

Garcea G, Berry D, Jones D, Singh R, Dennison A, Farmer P . Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005; 14(1):120-5. View

Chinen T, Kannan A, Levine A, Fan X, Klein U, Zheng Y . An essential role for the IL-2 receptor in T cell function. Nat Immunol. 2016; 17(11):1322-1333. PMC: 5071159. DOI: 10.1038/ni.3540. View

10.

Shibata H, Yamakoshi H, Sato A, Ohori H, Kakudo Y, Kudo C . Newly synthesized curcumin analog has improved potential to prevent colorectal carcinogenesis in vivo. Cancer Sci. 2009; 100(5):956-60. PMC: 11158762. DOI: 10.1111/j.1349-7006.2009.01127.x. View

11.

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

12.

Rayburn E, Ezell S, Zhang R . Anti-Inflammatory Agents for Cancer Therapy. Mol Cell Pharmacol. 2010; 1(1):29-43. PMC: 2843097. DOI: 10.4255/mcpharmacol.09.05. View

13.

Konkel J, Zhang D, Zanvit P, Chia C, Zangarle-Murray T, Jin W . Transforming Growth Factor-β Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses. Immunity. 2017; 46(4):660-674. DOI: 10.1016/j.immuni.2017.03.015. View

14.

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

15.

Flavell R, Sanjabi S, Wrzesinski S, Licona-Limon P . The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010; 10(8):554-67. PMC: 3885992. DOI: 10.1038/nri2808. View

16.

Lee D, Lee M, Kim J . Curcumin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells. Anticancer Res. 2010; 29(12):5039-44. View

17.

Anand P, Thomas S, Kunnumakkara A, Sundaram C, Harikumar K, Sung B . Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 2008; 76(11):1590-611. DOI: 10.1016/j.bcp.2008.08.008. View

18.

Huehn J, Polansky J, Hamann A . Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?. Nat Rev Immunol. 2008; 9(2):83-9. DOI: 10.1038/nri2474. View

19.

Mahara K, Kato J, Terui T, Takimoto R, Horimoto M, Murakami T . Transforming growth factor beta 1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue. Br J Cancer. 1994; 69(4):777-83. PMC: 1968800. DOI: 10.1038/bjc.1994.147. View

20.

Xu L, Zhang Y, Tian K, Chen X, Zhang R, Mu X . Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects. J Exp Clin Cancer Res. 2018; 37(1):261. PMC: 6206930. DOI: 10.1186/s13046-018-0929-6. View