TPD7 Inhibits the Growth of Cutaneous T Cell Lymphoma H9 Cell Through Regulating IL-2R Signalling Pathway

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2019 Nov 20

PMID 31742861

Citations 4

Authors

Man Zhu

Liu Yang

Xianpeng Shi

Zhengyan Gong

Runze Yu

Dongdong Zhang

Yanmin Zhang

Weina Ma

Affiliations

Soon will be listed here.

Abstract

IL-2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti-cancer effect. Here, we demonstrated the anti-cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL-2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL-2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL-2R and down-regulated the mRNA and protein levels of IL-2R. Furthermore, TPD7 suppressed the downstream cascades of IL-2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl-2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti-cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL-2R signalling pathway.

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TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway.

Zhu M, Yang L, Shi X, Gong Z, Yu R, Zhang D J Cell Mol Med. 2019; 24(1):984-995.

PMID: 31742861 PMC: 6933353. DOI: 10.1111/jcmm.14810.

References

Gaffen S . Signaling domains of the interleukin 2 receptor. Cytokine. 2001; 14(2):63-77. DOI: 10.1006/cyto.2001.0862. View

Smith G, Uchida K, Weiss A, Taunton J . Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat Chem Biol. 2016; 12(5):373-9. PMC: 4837022. DOI: 10.1038/nchembio.2056. View

Foss F, Demierre M, DiVenuti G . A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2005; 106(2):454-7. DOI: 10.1182/blood-2004-11-4570. View

Krejsgaard T, Lindahl L, Mongan N, Wasik M, Litvinov I, Iversen L . Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover. Semin Immunopathol. 2016; 39(3):269-282. PMC: 5368200. DOI: 10.1007/s00281-016-0594-9. View

Arenas-Ramirez N, Woytschak J, Boyman O . Interleukin-2: Biology, Design and Application. Trends Immunol. 2015; 36(12):763-777. DOI: 10.1016/j.it.2015.10.003. View

Kohnken R, Wen J, Mundy-Bosse B, McConnell K, Keiter A, Grinshpun L . Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma. Blood. 2017; 131(7):771-781. PMC: 5814934. DOI: 10.1182/blood-2017-09-805663. View

Zhao C, Tao T, Yang L, Qin Q, Wang Y, Liu H . Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer. Cancer Lett. 2019; 453:107-121. DOI: 10.1016/j.canlet.2019.03.043. View

Liao W, Lin J, Leonard W . Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013; 38(1):13-25. PMC: 3610532. DOI: 10.1016/j.immuni.2013.01.004. View

Gootenberg J, Ruscetti F, Mier J, Gazdar A, Gallo R . Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor. J Exp Med. 1981; 154(5):1403-18. PMC: 2186515. DOI: 10.1084/jem.154.5.1403. View

10.

Zhu M, Yang L, Shi X, Gong Z, Yu R, Zhang D . TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway. J Cell Mol Med. 2019; 24(1):984-995. PMC: 6933353. DOI: 10.1111/jcmm.14810. View

11.

Yu Z, Tian X, Peng Y, Sun Z, Wang C, Tang N . Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin-induced apoptosis in neural cancer cells. J Pineal Res. 2018; 65(1):e12478. DOI: 10.1111/jpi.12478. View

12.

Durham G, Williams J, Nasim M, Palmer T . Targeting SOCS Proteins to Control JAK-STAT Signalling in Disease. Trends Pharmacol Sci. 2019; 40(5):298-308. DOI: 10.1016/j.tips.2019.03.001. View

13.

Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014; 14(11):736-46. DOI: 10.1038/nrc3818. View

14.

Llavero F, Artaso A, Lacerda H, Parada L, Zugaza J . Lck/PLCγ control migration and proliferation of interleukin (IL)-2-stimulated T cells via the Rac1 GTPase/glycogen phosphorylase pathway. Cell Signal. 2016; 28(11):1713-24. DOI: 10.1016/j.cellsig.2016.07.014. View

15.

Nuzzo A, Giuffrida D, Masturzo B, Mele P, Piccoli E, Eva C . Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise. Cell Cycle. 2016; 16(2):200-212. PMC: 5283823. DOI: 10.1080/15384101.2016.1261766. View

16.

Kontro M, Kumar A, Majumder M, Eldfors S, Parsons A, Pemovska T . HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia. 2016; 31(2):301-309. DOI: 10.1038/leu.2016.222. View

17.

Choi J, Choi B, Shim J, Lee E, Kim D, Bang D . IL-2/IL-2 antibody immune complex regulates HSV-induced inflammation through induction of IL-2 receptor alpha, beta, and gamma in a mouse model. Immunobiology. 2015; 220(12):1381-92. DOI: 10.1016/j.imbio.2015.07.004. View

18.

Chihara D, Kagami Y, Kato H, Yoshida N, Kiyono T, Okada Y . IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma. Leuk Res. 2014; 38(5):608-12. DOI: 10.1016/j.leukres.2014.03.003. View

19.

Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue E . Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013; 381(9884):2167-75. DOI: 10.1016/S0140-6736(12)62190-4. View

20.

Flynn M, Hartley J . The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. Br J Haematol. 2017; 179(1):20-35. DOI: 10.1111/bjh.14770. View