ZHANG Dong, DENG Tongxing, WANG Fenggang, et al. Effects of Lentinan on Proliferation, Migration and Chemotherapy Sensitivity of Pancreatic Cancer Cells through the IL-6/STAT3/Notch Signaling Pathway[J]. Science and Technology of Food Industry, 2023, 44(24): 334−340. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2023020007.
Citation: ZHANG Dong, DENG Tongxing, WANG Fenggang, et al. Effects of Lentinan on Proliferation, Migration and Chemotherapy Sensitivity of Pancreatic Cancer Cells through the IL-6/STAT3/Notch Signaling Pathway[J]. Science and Technology of Food Industry, 2023, 44(24): 334−340. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2023020007.

Effects of Lentinan on Proliferation, Migration and Chemotherapy Sensitivity of Pancreatic Cancer Cells through the IL-6/STAT3/Notch Signaling Pathway

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  • Received Date: February 01, 2023
  • Available Online: October 15, 2023
  • Objective: Lentinan (LNT) had been shown to have direct cytotoxicity on cancer cells. However, the mechanism of this anti-tumor effect was still unclear. The purpose of this study was to investigate the effect of lentinan on the proliferation, migration and chemosensitivity of pancreatic cancer cells and its mechanism. Methods: Capan-1 cells from pancreatic cancer were randomly divided into control group, IL-6 group and IL-6+LNT group. Cell survival rate was detected by MTT, expression levels of p-STAT3, STAT3, Notch1 and Hes1 were analyzed by Western blot, and cell migration was observed by Transwell test. The cisplatin resistant cell model (Capan-1/DDP) was established, and the semi-inhibitory concentration of cisplatin (IC50) was detected in each group, and the relative expression levels of Ki67, MMP-9, MRP1 and P-gp were analyzed. Capan-1/DDP cell line was selected for tumor formation test in nude mice to verify the effects of LNT on tumor weight and IL-6/STAT3/Notch signaling pathway in nude mice. Results: Lentinan (7.5~240 µg/mL) could inhibit proliferation of pancreatic cancer cells. Compared with the IL-6 group, the expression levels of p-STAT3/STAT3, Notch1 and Hes1 in IL-6+LNT group were significantly down-regulated, the proliferation rate and the migration level was significantly dcreased (P<0.05, P<0.01). The proliferation rate of Capan-1/DDP cell line, IC50 and the expression levels of Ki-67, MMP-9, MRP1 and P-gp in IL-6+LNT group were significantly down-regulated (P<0.05, P<0.01). In vivo experiments, compared with IL-6 group, the tumor volume and tumor weight in cisplatin+IL-6 group and LNT+IL-6 group was significantly down-regulated, and expression levels of p-STAT3/STAT3, Notch1 and Hes1 were significantly decreased (P<0.05, P<0.01). Conclusion: LNT inhibits proliferation, migration and drug resistance of Capan-1 pancreatic cancer cells, which is related to the regulation of IL-6/STAT3/Notch signal pathway.
  • [1]
    PARK J K, HANK T, SCHERBER C M, et al. Primary and metastatic pancreatic cancer cells exhibit differential migratory potentials[J]. Pancreas,2020,49(1):128−134. doi: 10.1097/MPA.0000000000001459
    [2]
    CHANG C D, CHAO M W, LEE H Y, et al. In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer[J]. Journal of EnzymeInhibition and Medicinal Chemistry,2023,38(1):2166039.
    [3]
    YANG B S, QUAN Y N, ZHAO W L, et al. Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2, 3-d]pyrimidine derivatives as CDK inhibitors[J]. Journal of EnzymeInhibition and Medicinal Chemistry, 2023, 38(1):2169282.
    [4]
    RUPERT J E, NARASIMHAN A, JENGELLEY D H A, et al. Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia[J]. Journal of Experimental Medicine,2021,218(6):e20190450. doi: 10.1084/jem.20190450
    [5]
    MACE T A, SHAKYA R, PITARRESI J R, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer[J]. Gut,2018,67(2):320−332. doi: 10.1136/gutjnl-2016-311585
    [6]
    MA T, WANG D Y, WU J J, et al. KCTD10 functions as a tumor suppressor in hepatocellular carcinoma by triggering the Notch signaling pathway[J]. American Journal of Translational Research,2023,15(1):125−137.
    [7]
    ELBAKRY M M M, ELBAKWRY N M, HAGAG S A, et al. Pomegranate peel extract sensitizes hepatocellular carcinoma cells to ionizing radiation, induces apoptosis and inhibits mapk, jak/stat3, β-catenin/notch, and socs3 signaling[J]. Integrative Cancer Therapies, 2023, 22:15347354221151021.
    [8]
    TAO S F, CHEN Q, LIN C, et al. Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway[J]. Journal of Experimental & Clinical Cancer Research,2020,39(1):191.
    [9]
    PENG C Y, YU C C, HUANG C C, et al. Magnolol inhibits cancer stemness and IL-6/Stat3 signaling in oral carcinomas[J]. Journal of the Formosan Medical Association,2022,121(1):51−57. doi: 10.1016/j.jfma.2021.01.009
    [10]
    VAN DUIJNEVELDT G, GRIFFIN M D W, PUTOCZKI T L. Emerging roles for the IL-6 family of cytokines in pancreatic cancer[J]. Clinical Science,2020,134(16):2091−2115. doi: 10.1042/CS20191211
    [11]
    ZHANG M, ZHANG Y R, ZHANG L J, et al. Mushroom polysaccharide lentinan for treating different types of cancers:A review of 12 years clinical studies in China[J]. Progress in Molecular Biology and Translational Science,2019,163:297−328.
    [12]
    LIU H J, QIN Y, ZHAO Z H, et al. Lentinan-functionalized selenium nanoparticles target tumor cell mitochondria via TLR4/TRAF3/MFN1 pathway[J]. Theranostics,2020,10(20):9083−9099. doi: 10.7150/thno.46467
    [13]
    SHIMIZU K, WATANABE S, WATANABE S, et al. Efficacy of oral administered superfine dispersed lentinan for advanced pancreatic cancer[J]. Hepato-Gastroenterology,2009,56(89):240−244.
    [14]
    HU B, ZHANG K D, LI S B, et al. HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer[J]. Cancer Letters,2016,376(2):387−398. doi: 10.1016/j.canlet.2016.04.013
    [15]
    CHEN S Y, CAI K, ZHENG D J, et al. RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the notch signaling pathway[J]. Cell Death & Disease,2022,13(11):945.
    [16]
    张彩芳, 秦令祥, 周婧琦, 等. 基于响应面法优化双酶耦合超高压提取香菇多糖工艺及抗氧化活性研究[J]. 中国食品添加剂,2022,33(9):69−74. [ZHANG C F, QIN L X, ZHOU J Q, et al. Optimization of double enzymes coupling ultra high pressure extraction process of lentinan by response surface method and its antioxidant activity[J]. China Food Additives,2022,33(9):69−74.]

    ZHANG C F, QIN L X, ZHOU J Q, et al. Optimization of double enzymes coupling ultra high pressure extraction process of lentinan by response surface method and its antioxidant activity[J]. China Food Additives, 2022, 33(9): 69−74.
    [17]
    苏华, 赵玉梅, 陈静, 等. 香菇多糖联合AC方案、紫杉醇对晚期三阴性乳腺癌患者生存情况及PF4、MK、Ki-67表达的影响[J]. 临床医学研究与实践,2023,8(4):55−57. [SU H, ZHAO Y M, CHEN J, et al. Effects of lentinan combined with AC regimen and paclitaxel on survival and expression of PF4, MK and Ki-67 in patients with advanced triple negative breast cancer[J]. Clinical Research and Practice,2023,8(4):55−57.]

    SU H, ZHAO Y M, CHEN J, et al. Effects of lentinan combined with AC regimen and paclitaxel on survival and expression of PF4, MK and Ki-67 in patients with advanced triple negative breast cancer[J]. Clinical Research and Practice, 2023, 8(4): 55−57.
    [18]
    MENG M J, HUO R, WANG Y, et al. Lentinan inhibits oxidative stress and alleviates LPS-induced inflammation and apoptosis of BMECs by activating the Nrf2 signaling pathway[J]. International Journal of Biological Macromolecules, 2022, 222(Pt B):2375−2391.
    [19]
    IBRAHIM S A, GADALLA R, EI-GHONAIMY E A, et al. Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways[J]. Molecular Cancer,2017,16(1):57. doi: 10.1186/s12943-017-0621-z
    [20]
    HUNG L, HU B, NI J B, et al. Retraction note:Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis[J]. 2023, 42(1):18.
    [21]
    JI N, YU Z L. IL-6/Stat3 suppresses osteogenic differentiation in ossification of the posterior longitudinal ligament via miR-135b-mediated BMPER reduction[J]. Cell and Tissue Research,2023,391(1):145−157. doi: 10.1007/s00441-022-03694-x
    [22]
    杜晓鹃, 李学军, 李素婷, 等. IL-6调控TLR4/NF-κB炎症信号促进人胰腺癌细胞增殖的实验研究[J]. 现代预防医学, 2019, 46(15):2810-2815. [DU X J, LI X J, LI S T, et al. IL-6 promotes the proliferation of human pancreatic cancer BxPC-3 cells via the activation of TLR4/NF-κB signaling pathway[J]. Modern Preventive Medicine, 2019, 46(15):2810-2815.]

    DU X J, LI X J, LI S T, et al. IL-6 promotes the proliferation of human pancreatic cancer BxPC-3 cells via the activation of TLR4/NF-κB signaling pathway[J]. Modern Preventive Medicine, 2019, 46(15): 2810-2815.
    [23]
    HE Y L, GUO X R, LAN T Y, et al. Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling[J]. Stem Cell Research & Therapy,2021,12(1):396.
    [24]
    谢娅, 张嘉琳, 李亚南, 等. 二甲双胍通过抑制IL-6/NF-κB/P-gp改善卵巢癌PARP抑制剂耐药[J]. 郑州大学学报(医学版),2023,58(2):175−182. [XIE Y, ZHANG J L, LI Y N, et al. Metformin improves PARP inhibitor resistance in ovarian cancer by inhibiting IL-6/NF-κB/P-gp[J]. Journal of Zhengzhou University(Medical Sciences),2023,58(2):175−182.]

    XIE Y, ZHANG J L, LI Y N, et al. Metformin improves PARP inhibitor resistance in ovarian cancer by inhibiting IL-6/NF-κB/P-gp[J]. Journal of Zhengzhou University(Medical Sciences), 2023, 58(2): 175−182.
    [25]
    ZOU M H, ZHANG X Q, XU C H. IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in ovarian cancer cells[J]. Cellular Oncology,2016,39(1):47−57. doi: 10.1007/s13402-015-0251-7
    [26]
    MIYAKE M, NAKAI D. Effect of proinflammatory cytokine IL-6 on efflux transport of rebamipide in Caco-2 cells[J]. Xenobiotica,2017,47(9):821−824. doi: 10.1080/00498254.2016.1229085
    [27]
    ZHAO X F, LI Y F, DU K, et al. Involvement of human and canine MRP1 and MRP4 in benzylpenicillin transport[J]. PLoS One,2019,14(11):e0225702. doi: 10.1371/journal.pone.0225702
    [28]
    YIN Z, MA T T, LIN Y, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma[J]. Journal of Cellular Biochemistry,2018,119(11):9419−9432. doi: 10.1002/jcb.27259
    [29]
    张晶, 苏畅, 孔凡铭, 等. 基于IKKβ/NF-κB通路探究香菇多糖联合顺铂对乳腺癌的干预作用[J]. 现代药物与临床,2022,37(9):1932−1937. [ZHANG J, SU C, KONG F M, et al. Explore the intervention effect of lentinan combined with cisplatin on breast cancer based on IKKβ/NF-κB pathway[J]. Drugs & Clinic,2022,37(9):1932−1937.]

    ZHANG J, SU C, KONG F M, et al. Explore the intervention effect of lentinan combined with cisplatin on breast cancer based on IKKβ/NF-κB pathway[J]. Drugs & Clinic, 2022, 37(9): 1932−1937.
    [30]
    LI M, DU X, YUAN Z, et al. Lentinan triggers oxidative stress-mediated anti-inflammatory responses in lung cancer cells[J]. Molecular and Cellular Biochemistry,2022,477(2):469−477. doi: 10.1007/s11010-021-04293-0
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