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Investigational New Drugs

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28.09.2020 | PRECLINICAL STUDIES

rAj-Tspin, a novel recombinant peptide from Apostichopus japonicus, suppresses the proliferation, migration, and invasion of BEL-7402 cells via a mechanism associated with the ITGB1-FAK-AKT pathway

verfasst von: Ping Yu, Rui Wu, Zunchun Zhou, Xin Zhang, Ruoshu Wang, Xueting Wang, Sen Lin, Jihong Wang, Li Lv

Erschienen in: Investigational New Drugs | Ausgabe 2/2021

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Summary

Purpose Our study aimed to investigate the antitumor effects of rAj-Tspin on BEL-7402 hepatocellular carcinoma cells and to explore the underlying mechanism. Method For the in vivo experiment, BEL-7402 cells were inoculated subcutaneously into the axilla of nude mice to generate a BEL-7402 cell-bearing model, and model mice were then treated with different doses of rAj-Tspin. A CCK-8 assay was used to evaluate the in vitro viability of BEL-7402 and LO2 cells after treatment with different concentrations of rAj-Tspin. The effects of rAj-Tspin on BEL-7402 cell apoptosis, migration and invasion were evaluated by AO/EB and Hoechst fluorescent staining and by scratch and Transwell assays, and the tumor-suppressive mechanism of rAj-Tspin was explored by Western blotting. Results rAj-Tspin suppressed the proliferation of BEL-7402 cells with an IC₅₀ of 0.89 μM. The results of both microscopic analysis and Western blotting suggested that rAj-Tspin induced the apoptosis of BEL-7402 cells through a mitochondria-dependent pathway. Furthermore, rAj-Tspin disrupted EMT; this disruption ultimately caused BEL-7402 cells to lose their shape and decreased their migration and invasion. Moreover, rAj-Tspin might inhibit the proliferation and metastasis of BEL-7402 cells through the ITGB1-FAK-AKT pathway. Conclusion rAj-Tspin exerts an antitumor effect through the ITGB1-FAK-Akt signaling pathway and exhibits low toxicity at an effective dose.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRefPubMed

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144(8):1941–1953. https://doi.org/10.1002/ijc.31937CrossRefPubMed

Sia D, Villanueva A, Friedman SL, Llovet JM (2017) Liver Cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152(4):745–761. https://doi.org/10.1053/j.gastro.2016.11.048CrossRefPubMed

Benson AB 3rd, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Saenz DA, Are C, Brown DB, Chang DT, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Schmidt C, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Zhu AX, Hoffmann KG, Darlow S (2017) NCCN guidelines insights: Hepatobiliary cancers, version 1.2017. J Natl Compr Cancer Netw 15(5):563–573. https://doi.org/10.6004/jnccn.2017.0059CrossRef

Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, Anders R, Are C, Brown D, Chang DT, Cloyd J, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Hammond LJ, Darlow SD (2019) Guidelines insights: Hepatobiliary cancers, version 2.2019. J Natl Compr Cancer Netw 17(4):302–310. https://doi.org/10.6004/jnccn.2019.0019CrossRef

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379(1):54–63. https://doi.org/10.1056/NEJMoa1717002CrossRefPubMedPubMedCentral

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim T-Y, Choo S-P, Trojan J, Welling TH, Meyer T, Kang Y-K, Yeo W, Chopra A, Anderson J, dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502. https://doi.org/10.1016/s0140-6736(17)31046-2CrossRefPubMedPubMedCentral

Correia-da-Silva M, Sousa E, Pinto MMM, Kijjoa A (2017) Anticancer and cancer preventive compounds from edible marine organisms. Semin Cancer Biol 46:55–64. https://doi.org/10.1016/j.semcancer.2017.03.011CrossRefPubMed

Morley JE, Armbrecht HJ, Farr SA, Kumar VB (2012) The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer's disease. Biochim Biophys Acta 1822(5):650–656. https://doi.org/10.1016/j.bbadis.2011.11.015CrossRefPubMed

10.

Li Q, Cai C, Chang Y, Zhang F, Linhardt RJ, Xue C, Li G, Yu G (2018) A novel structural fucosylated chondroitin sulfate from Holothuria Mexicana and its effects on growth factors binding and anticoagulation. Carbohydr Polym 181:1160–1168. https://doi.org/10.1016/j.carbpol.2017.10.100CrossRefPubMed

11.

Kim SJ, Park SY, Hong SM, Kwon EH, Lee TK (2016) Skin whitening and anti-corrugation activities of glycoprotein fractions from liquid extracts of boiled sea cucumber. Asian Pac J Trop Med 9(10):1002–1006. https://doi.org/10.1016/j.apjtm.2016.08.001CrossRefPubMed

12.

Shao F, Lv M, Zheng Y, Jiang J, Wang Y, Lv L, Wang J (2015) The anti-tumour activity of rLj-RGD4, an RGD toxin protein from Lampetra japonica, on human laryngeal squamous carcinoma Hep-2 cells in nude mice. Biochimie 119:183–191. https://doi.org/10.1016/j.biochi.2015.11.004CrossRefPubMed

13.

Wang Y, Zheng Y, Tu Z, Dai Y, Xu H, Lv L, Wang J (2017) The anti-tumor effects of the recombinant toxin protein rLj-RGD3 from Lampetra japonica on pancreatic carcinoma Panc-1 cells in nude mice. Peptides 88:8–17. https://doi.org/10.1016/j.peptides.2016.12.007CrossRefPubMed

14.

Zheng Y, Lv L, Yi L, Wu R, Xiao R, Wang J (2017) rLj-RGD3 suppresses the growth of HeyA8 cells in nude mice. Molecules 22(12). https://doi.org/10.3390/molecules22122234

15.

Lorenz L, Axnick J, Buschmann T, Henning C, Urner S, Fang S, Nurmi H, Eichhorst N, Holtmeier R, Bodis K, Hwang JH, Mussig K, Eberhard D, Stypmann J, Kuss O, Roden M, Alitalo K, Haussinger D, Lammert E (2018) Mechanosensing by beta1 integrin induces angiocrine signals for liver growth and survival. Nature 562(7725):128–132. https://doi.org/10.1038/s41586-018-0522-3CrossRefPubMed

16.

Zhang PF, Li KS, Shen YH, Gao PT, Dong ZR, Cai JB, Zhang C, Huang XY, Tian MX, Hu ZQ, Gao DM, Fan J, Ke AW, Shi GM (2016) Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis 7:e2201. https://doi.org/10.1038/cddis.2015.324CrossRefPubMedPubMedCentral

17.

Poon RT, Chung KK, Cheung ST, Lau CP, Tong SW, Leung KL, Yu WC, Tuszynski GP, Fan ST (2004) Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma. Clin Cancer Res 10(12 Pt 1):4150–4157. https://doi.org/10.1158/1078-0432.CCR-03-0435CrossRefPubMed

18.

Venkatraman L, Tucker-Kellogg L (2013) The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells. Liver Int 33(9):1386–1397. https://doi.org/10.1111/liv.12231CrossRefPubMedPubMedCentral

19.

Chavez-Tapia NC, Rosso N, Tiribelli C (2012) Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease. BMC Gastroenterol 12:20. https://doi.org/10.1186/1471-230X-12-20CrossRefPubMedPubMedCentral

20.

Li Y, Turpin CP, Wang S (2017) Role of thrombospondin 1 in liver diseases. Hepatol Res 47(2):186–193. https://doi.org/10.1111/hepr.12787CrossRefPubMed

21.

Yang D, Zhang Q, Ma Y, Che Z, Zhang W, Wu M, Wu L, Liu F, Chu Y, Xu W, McGrath M, Song C, Liu J (2019) Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis. EBioMedicine. 47:114–127. https://doi.org/10.1016/j.ebiom.2019.08.068CrossRefPubMedPubMedCentral

22.

Duan S, Yu S, Yuan T, Yao S, Zhang L (2019) Exogenous let-7a-5p induces A549 lung Cancer cell death through BCL2L1-mediated PI3Kgamma signaling pathway. Front Oncol 9:808. https://doi.org/10.3389/fonc.2019.00808CrossRefPubMedPubMedCentral

23.

Nguyen TTT, Ishida CT, Shang E, Shu C, Torrini C, Zhang Y, Bianchetti E, Sanchez-Quintero MJ, Kleiner G, Quinzii CM, Westhoff MA, Karpel-Massler G, Canoll P, Siegelin MD (2019) Activation of LXRbeta inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition. EMBO Mol med:e10769. https://doi.org/10.15252/emmm.201910769

24.

Li X, Luo S, Zhang J, Yuan Y, Jiang W, Zhu H, Ding X, Zhan L, Wu H, Xie Y, Song R, Pan Z, Lu Y (2019) lncRNA H19 alleviated myocardial I/RI via suppressing miR-877-3p/Bcl-2-mediated mitochondrial apoptosis. Mol Ther Nucleic Acids 17:297–309. https://doi.org/10.1016/j.omtn.2019.05.031CrossRefPubMedPubMedCentral

25.

Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18(2):128–134. https://doi.org/10.1038/nrc.2017.118CrossRefPubMed

26.

Jin H, He Y, Zhao P, Hu Y, Tao J, Chen J, Huang Y (2019) Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery. Theranostics 9(1):265–278. https://doi.org/10.7150/thno.27246CrossRefPubMedPubMedCentral

27.

Jinsong L (2019) The "life code": a theory that unifies the human life cycle and the origin of human tumors. Semin Cancer Biol 60:380–397. https://doi.org/10.1016/j.semcancer.2019.09.005CrossRef

28.

Lopez-Ramirez MA, Fonseca G, Zeineddine HA, Girard R, Moore T, Pham A, Cao Y, Shenkar R, de Kreuk BJ, Lagarrigue F, Lawler J, Glass CK, Awad IA, Ginsberg MH (2017) Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J Exp Med 214(11):3331–3346. https://doi.org/10.1084/jem.20171178CrossRefPubMedPubMedCentral

29.

Huang W, Yu D, Wang M, Han Y, Lin J, Wei D, Cai J, Li B, Chen P, Zhang X (2020) ITGBL1 promotes cell migration and invasion through stimulating the TGF-beta signalling pathway in hepatocellular carcinoma. Cell Prolif 53(7):e12836. https://doi.org/10.1111/cpr.12836CrossRefPubMedPubMedCentral

30.

Daubon T, Leon C, Clarke K, Andrique L, Salabert L, Darbo E, Pineau R, Guerit S, Maitre M, Dedieu S, Jeanne A, Bailly S, Feige JJ, Miletic H, Rossi M, Bello L, Falciani F, Bjerkvig R, Bikfalvi A (2019) Deciphering the complex role of thrombospondin-1 in glioblastoma development. Nat Commun 10(1):1146. https://doi.org/10.1038/s41467-019-08480-yCrossRefPubMedPubMedCentral

31.

Yang HD, Kim HS, Kim SY, Na MJ, Yang G, Eun JW, Wang HJ, Cheong JY, Park WS, Nam SW (2019) HDAC6 suppresses let-7i-5p to elicit TSP1/CD47-mediated anti-tumorigenesis and phagocytosis of hepatocellular carcinoma. Hepatology 70(4):1262–1279. https://doi.org/10.1002/hep.30657CrossRefPubMed

32.

Shen J, Cao B, Wang Y, Ma C, Zeng Z, Liu L, Li X, Tao D, Gong J, Xie D (2018) Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. J Exp Clin Cancer Res 37(1):175. https://doi.org/10.1186/s13046-018-0850-zCrossRefPubMedPubMedCentral

33.

Yamashiro Y, Thang BQ, Ramirez K, Shin SJ, Kohata T, Ohata S, Nguyen TAV, Ohtsuki S, Nagayama K, Yanagisawa H (2020) Matrix mechanotransduction mediated by thrombospondin-1integrinYAP in the vascular remodeling. Proc Natl Acad Sci U S A 117(18):9896–9905. https://doi.org/10.1073/pnas.1919702117CrossRefPubMedPubMedCentral

34.

Xie Y, Du J, Liu Z, Zhang D, Yao X, Yang Y (2019) MiR-6875-3p promotes the proliferation, invasion and metastasis of hepatocellular carcinoma via BTG2/FAK/Akt pathway. J Exp Clin Cancer Res 38(1):7. https://doi.org/10.1186/s13046-018-1020-zCrossRefPubMedPubMedCentral

35.

Zhang J, Chen Y, Lin J, Jia R, An T, Dong T, Zhang Y, Yang X (2020) Cyclovirobuxine D exerts anticancer effects by suppressing the EGFR-FAK-AKT/ERK1/2-slug signaling pathway in human hepatocellular carcinoma. DNA Cell Biol 39(3):355–367. https://doi.org/10.1089/dna.2019.4990CrossRefPubMed

Titel: rAj-Tspin, a novel recombinant peptide from Apostichopus japonicus, suppresses the proliferation, migration, and invasion of BEL-7402 cells via a mechanism associated with the ITGB1-FAK-AKT pathway
verfasst von: Ping Yu
Rui Wu
Zunchun Zhou
Xin Zhang
Ruoshu Wang
Xueting Wang
Sen Lin
Jihong Wang
Li Lv
Publikationsdatum: 28.09.2020
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 2/2021
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-020-01008-y

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rAj-Tspin, a novel recombinant peptide from Apostichopus japonicus, suppresses the proliferation, migration, and invasion of BEL-7402 cells via a mechanism associated with the ITGB1-FAK-AKT pathway

Summary

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Springer Medizin

Summary

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