Galectin-9 inhibits cell proliferation and induces apoptosis in Jurkat and KE-37 acute lymphoblastic leukemia cell lines via caspase-3 activation

Narges Zargar Balajam , Mahdi Shabani, Mahmoud Aghaei

Abstract


Background and purpose: Acute lymphoblastic leukemia (ALL) is a type of cancer of blood and bone marrow characterized by abnormal proliferation of lymphoid progenitor cells. Galectin-9 is a tandem-repeat type galectin expressed in various tumor cells. It seems that the connection between galectin-9 and T cell immunoglobulin mucin-3 receptor acts as a negative regulator of cancer cells proliferation.

Experimental approach: In this research, the effects of galectin-9 were investigated using MTS cell proliferation colorimetric, colony-forming, annexin V-FITC/PI, and caspase-3 assays in the Jurkat and KE-37 cell lines of ALL. Furthermore, the western blotting technique was used to evaluate the levels of apoptotic proteins such as Bax and Bcl-2 in these cell lines.

Findings/Results: Our results indicated that galectin-9 can considerably reduce the cell growth and colony formation ability of both Jurkat and KE-37 cell lines in a concentration-dependent manner. Besides, galectin-9 induced apoptosis in a concentration-dependent manner in ALL cells by a mechanism associated with Bax/Bcl-2 expression and activation of the caspase-3 activation.

Conclusion and implications: Galectin-9 inhibited the growth and proliferation of cell lines with increased programmed cell death, therefore it can be considered as a potential factor in the progression of ALL therapeutics that needs more research in this context.


Keywords


Acute lymphoblastic leukemia; Apoptosis; Galectin-9; T-cell immunoglobulin,mucin-domain 3.

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References


Paul S, Kantarjian H, Jabbour EJ. Adult acute lymphoblastic leukemia. Mayo Clin Proc. 2016;91(11):1645-1666.

DOI: 10.1016/j.mayocp.2016.09.010.

Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, et al. SEER cancer statistics review, 1975-2013. National Cancer Institute. Bethesda, MD:NCI. 2016;8.19. Available from: https://seer.cancer.gov/archive/csr/1975_2013/.

Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, et al. Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood. 2009;113(9):1957-1966.

DOI: 10.1182/blood-2008-02-142596.

Thijssen VL, Heusschen R, Caers J, Griffioen AW. Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta. 2015;1855(2):235-247.

DOI: 10.1016/j.bbcan.2015.03.003.

Chou FC, Chen HY, Kuo CC, Sytwu HK. Role of galectins in tumors and in clinical immunotherapy. Int J Mol Sci. 2018;19(2):430-441.

DOI: 10.3390/ijms19020430.

Elahi S, Niki T, Hirashima M, Horton H. Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection. Blood. 2012;119(18):4192-4204.

DOI: 10.1182/blood-2011-11-389585.

Oomizu S, Arikawa T, Niki T, Kadowaki T, Ueno M, Nishi N, et al. Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner. Clin Immunol. 2012;143(1):51-58.

DOI: 10.1016/j.clim.2012.01.004.

Madireddi S, Eun SY, Mehta AK, Birta A, Zajonc DM, Niki T, et al. Regulatory T cell-mediated suppression of inflammation induced by DR3 signaling is dependent on galectin-9. J Immunol. 2017;199(8):2721-2728.

DOI: 10.4049/jimmunol.1700575.

Nobumoto A, Nagahara K, Oomizu S, Katoh S, Nishi N, Takeshita K, et al. Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices. Glycobiology. 2008;18(9):735-744.

DOI: 10.1093/glycob/cwn062.

Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, et al. Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer. Clin Cancer Res. 2005;11(8):2962-2968.

DOI: 10.1158/1078-0432.CCR-04-0861.

Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, et al. Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma. Asian Pac J Cancer Prev. 2012;13(6):2503-2509.

DOI: 10.7314/apjcp.2012.13.6.2503.

Kang CW, Dutta A, Chang LY, Mahalingam J, Lin YC, Chiang JM, et al. Apoptosis of tumor infiltrating effector TIM-3+ CD8+ T cells in colon cancer. Sci Rep. 2015;5:15659,1-12.

DOI: 10.1038/srep15659.

Fujita K, Iwama H, Sakamoto T, Okura R, Kobayashi K, Takano J, et al. Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo. Int J Oncol. 2015;46(6):2419-2430.

DOI: 10.3892/ijo.2015.2941.

Kobayashi K, Morishita A, Iwama H, Fujita K, Okura R, Fujihara S, et al. Galectin-9 suppresses cholangiocarcinoma cell proliferation by inducing apoptosis but not cell cycle arrest. Oncol Rep. 2015;34(4):1761-1770.

DOI: 10.3892/or.2015.4197.

Tadokoro T, Morishita A, Fujihara S, Iwama H, Niki T, Fujita K, et al. Galectin-9: an anticancer molecule for gallbladder carcinoma. Int J Oncol. 2016;48(3):1165-1174.

DOI: 10.3892/ijo.2016.3347.

Takano J, Morishita A, Fujihara S, Iwama H, Kokado F, Fujikawa K, et al. Galectin-9 suppresses the proliferation of gastric cancer cells in vitro. Oncol Rep. 2016;35(2):851-860.

DOI: 10.3892/or.2015.4452.

Kuroda J, Yamamoto M, Nagoshi H, Kobayashi T, Sasaki N, Shimura Y, et al. Targeting activating transcription factor 3 by galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia. Mol Cancer Res. 2010;8(7):994-1001.

DOI: 10.1158/1541-7786.MCR-10-0040.

Balajam NZ, Shabani M, Aghaei M, Haghighi M, Kompani F. Study of T-cell immunoglobulin and mucin domain-3 expression profile in peripheral blood and bone marrow of human acute lymphoblastic leukemia patients. J Res Med Sci. 2020;25: 69-74.

DOI: 10.4103/jrms.JRMS_759_19.

Shahali A, Ghanadian M, Jafari SM, Aghaei M. Mitochondrial and caspase pathways are involved in the induction of apoptosis by nardosinen in MCF-7 breast cancer cell line. Res Pharm Sci. 2018;13(1):12-21.

DOI: 10.4103/1735-5362.220963.

Jafari SM, Joshaghani HR, Panjehpour M, Aghaei M, Zargar Balajam N. Apoptosis and cell cycle regulatory effects of adenosine by modulation of GLI‐1 and ERK 1/2 pathways in CD 44+ and CD 24˗ breast cancer stem cells. Cell Prolif. 2017;50(4):e12345,1-12.

DOI: 10.1111/cpr.12345.

Jafari SM, Panjehpour M, Aghaei M, Joshaghani HR, Enderami SE. A3 Adenosine receptor agonist inhibited survival of breast cancer stem cells via GLI-1 and ERK1/2 pathway. J Cell Biochem. 2017;118(9):2909-2920.

DOI: 10.1002/jcb.25945.

Aghaei M, Panjehpour M, Karami-Tehrani F, Salami S. Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway. J Cancer Res Clin Oncol. 2011;137(10):1511-1523.

DOI: 10.1007/s00432-011-1031-z.

Azemikhah M, Ashtiani HA, Aghaei M, Rastegar H. Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues. Res Pharm Sci. 2015; 10:356-363.

PMID: 26600862.

Jafari SM, Nazri A, Shabani M, Balajam NZ, Aghaei M. Galectin-9 induces apoptosis in OVCAR-3 ovarian cancer cell through mitochondrial pathway. Res Pharm Sci. 2018;13(6):557-565.

DOI: 10.4103/1735-5362.245967.

Sakhnevych SS, Yasinska IM, Bratt AM, Benlaouer O, Gonçalves Silva I, Hussain R, et al. Cortisol facilitates the immune escape of human acute myeloid leukemia cells by inducing latrophilin 1 expression. Cell Mol Immunol. 2018;15:994-997.

DOI: 10.1038/s41423-018-0053-8.

Zhu C, Anderson AC, Kuchroo VK. TIM-3 and its regulatory role in immune responses. Curr Top Microbiol Immunol. 2011;350:1-15.

DOI: 10.1007/82_2010_84.

Baghdadi M, Jinushi M. The impact of the TIM gene family on tumor immunity and immunosuppression. Cell Mol Immunol. 2014;11(1):41-48.

DOI: 10.1038/cmi.2013.57.

Mattei F, Schiavoni G. TIM-3 as a molecular switch for tumor escape from innate immunity. Front Immunol. 2013;3:418-420.

DOI: 10.3389/fimmu.2012.00418.

Folgiero V, Cifaldi L, Li Pira G, Maria Goffredo B, Vinti L, Locatelli F. TIM-3/Gal-9 interaction induces IFNgamma-dependent IDO1 expression in acute myeloid leukemia blast cells. J Hematol Oncol. 2015;8:36-41.

DOI: 10.1186/s13045-015-0134-4.

Wang Z, Zhu J, Gu H, Yuan Y, Zhang B, Zhu D, et al. The clinical significance of abnormal Tim-3 expression on NK cells from patients with gastric cancer. Immunol Invest. 2015;44(6):578-589.

DOI: 10.3109/08820139.2015.1052145.

Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012;56(4):1342-1351.

DOI: 10.1002/hep.25777.

Tadokoro T, Fujihara S, Chiyo T, Oura K, Samukawa E, Yamana Y, et al. Induction of apoptosis by galectin-9 in liver metastatic cancer cells: in vitro study. Int J Oncol. 2017;51(2):607-614.

DOI: 10.3892/ijo.2017.4053.

Akashi E, Fujihara S, Morishita A, Tadokoro T, Chiyo T, Fujikawa K, et al. Effects of galectin-9 on apoptosis, cell cycle and autophagy in human esophageal adenocarcinoma cells. Oncol Rep. 2017;38(1):506-514.

DOI: 10.3892/or.2017.5689.

Roth CG, Garner K, Eyck ST, Boyiadzis M, Kane LP, Craig FE. TIM3 expression by leukemic and non‐leukemic myeloblasts. Cytometry B Clin Cytom. 2013;84(3):167-172.

DOI: 10.1002/cyto.b.21080.

Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, et al. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170(7):3631-3636.

DOI: 10.4049/jimmunol.170.7.3631.

Gonçalves Silva I, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine. 2017;22:44-57.

DOI: 10.1016/j.ebiom.2017.07.018.

Kuroda J, Yamamoto M, Nagoshi H, Kobayashi T, Sasaki N, Shimura Y, et al. Targeting activating transcription factor 3 by galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia. Mol Cancer Res. 2010;8(7):994-1001.

DOI: 10.1158/1541-7786.

Kageshita T, Kashio Y, Yamauchi A, Seki M, Abedin MJ, Nishi N, et al. Possible role of galectin-9 in cell aggregation and apoptosis of human melanoma cell lines and its clinical significance. Int J Cancer. 2002;99(6):809-816.

DOI: 10.1002/ijc.10436.

Chen S, Pu J, Bai J, Yin Y, Wu K, Wang J, et al. EZH2 promotes hepatocellular carcinoma progression through modulating miR-22/galectin-9 axis. J Exp Clin Cancer Res. 2018;37(1):3-14.

DOI: 10.1186/s13046-017-0670-6.

Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27(50):6398‐6406.

DOI: 10.1038/onc.2008.307.


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