Astragalus polysaccharide induces the apoptosis of human hepatocellular carcinoma cells by decreasing the expression of Notch1

  • Authors:
    • Wen-Hai Huang
    • Wei-Rong Liao
    • Rong-Xun Sun
  • View Affiliations

  • Published online on: June 9, 2016     https://doi.org/10.3892/ijmm.2016.2632
  • Pages: 551-557
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Abstract

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer death worldwide. Astragalus polysaccharide (APS), the primary active component extracted from a traditional Chinese medicinal herb Astragalus membranaceus, has been proved to exert a marked inhibitory effect on a number of types of human solid tumors. In the present study, we aimed to examine the effects of APS on the survival of the HCC cell line H22 and to elucidate the underlying regulatory mechanisms responsible for these effects. Our results revealed that the mRNA and protein expression of Notch1 was significantly upregulated in the HCC tissues compared with that in the normal tissues. APS decreased cell viability and induced the apoptosis of HCC cells in a concentration-dependent manner, which were evaluated using a cell counting kit-8 (CCK-8) assay and flow cytometric analysis, respectively. Furthermore, APS regulated the expression of apoptosis-related genes (Bcl-2 and BAX) and proteases (caspase-3 and -8). Mechanically, Notch1 expression was found to be suppressed in HCC cells, and further analysis indicated that Notch1 knockdown by siRNA significantly reduced cell viability, suppressed the metastatic capacity and enhanced the apoptosis of HCC cells. Taken together, these findings suggest that Notch1 may be a potential therapeutic target for the treatment of HCC.

References

1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

El-Serag HB and Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 340:745–750. 1999. View Article : Google Scholar : PubMed/NCBI

3 

Parkin DM, Bray F, Ferlay J and Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer. 94:153–156. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Fares N and Peron JM: Epidemiology, natural history, and risk factors of hepatocellular carcinoma. Rev Prat. 63:216–217. 220–222. 2013.In French.

6 

Cusnir M and Patt YZ: Novel systemic therapy options for hepatocellular carcinoma. Cancer J. 10:97–103. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Takayasu K, Arii S, Ikai I, Omata M, Okita K, Ichida T, Matsuyama Y, Nakanuma Y, Kojiro M, Makuuchi M and Yamaoka Y; Liver Cancer Study Group of Japan: Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology. 131:461–469. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Han SH, Reddy KR, Keeffe EB, Soldevila-Pico C, Gish R, Chung RT, Degertekin B and Lok A; NIH HBV OLT Study Group: Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study. Clin Transplant. 25:E152–E162. 2011. View Article : Google Scholar

9 

Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW and Weitz J: Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 253:453–469. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Hassan T, El-Shafie M, Helmy A, Ammar S and Attyia M: Liver resection for early stage hepatocellular carcinoma. SECI Oncology. 2015. View Article : Google Scholar

11 

Forner A, Hessheimer AJ, Isabel Real M and Bruix J: Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol. 60:89–98. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Silva MF and Wigg AJ: Current controversies surrounding liver transplantation for hepatocellular carcinoma. J Gastroenterol Hepatol. 25:1217–1226. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Sapisochin G, Castells L, Dopazo C, Bilbao I, Minguez B, Lázaro JL, Allende H, Balsells J, Caralt M and Charco R: Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg Oncol. 20:1194–1202. 2013. View Article : Google Scholar

14 

Guo L, Liu J, Hu Y, Wang D, Li Z, Zhang J, Qin T, Liu X, Liu C, Zhao X, et al: Astragalus polysaccharide and sulfated epimedium polysaccharide synergistically resist the immunosuppression. Carbohydr Polym. 90:1055–1060. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Li HQ, Reeve-Johnson L and Wang JD: Effect of Astragalus polysaccharides on erythrocyte immune adherence of chickens inoculated with infectious bursal disease virus. Agric Sci China. 6:1402–1408. 2007. View Article : Google Scholar

16 

Li R, Chen WC, Wang WP, Tian WY and Zhang XG: Antioxidant activity of Astragalus polysaccharides and antitumour activity of the polysaccharides and siRNA. Carbohydr Polym. 82:240–244. 2010. View Article : Google Scholar

17 

Jin M, Zhao K, Huang Q and Shang P: Structural features and biological activities of the polysaccharides from Astragalus membranaceus. Int J Biol Macromol. 64:257–266. 2014. View Article : Google Scholar

18 

Wang T, Sun Y, Jin L, Xu Y, Wang L, Ren T and Wang K: Enhancement of non-specific immune response in sea cucumber (Apostichopus japonicus) by Astragalus membranaceus and its polysaccharides. Fish Shellfish Immunol. 27:757–762. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Yin X, Chen L, Liu Y, Yang J, Ma C, Yao Z, Yang L, Wei L and Li M: Enhancement of the innate immune response of bladder epithelial cells by Astragalus polysaccharides through upregulation of TLR4 expression. Biochem Biophys Res Commun. 397:232–238. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Zhong R, Yu M, Liu H, Sun H, Cao Y and Zhou D: Effects of dietary Astragalus polysaccharide and Astragalus membra-naceus root supplementation on growth performance, rumen fermentation, immune responses, and antioxidant status of lambs. Anim Feed Sci Technol. 174:60–67. 2012. View Article : Google Scholar

21 

Chen Y, Song M, Wang Y, Xiong W, Zeng L, Zhang S, Xu M, Du H, Liu J, Wang D, et al: The anti-DHAV activities of Astragalus polysaccharide and its sulfate compared with those of BSRPS and its sulfate. Carbohydr Polym. 117:339–345. 2015. View Article : Google Scholar

22 

Huang X, Wang D, Hu Y, Lu Y, Guo Z, Kong X and Sun J: Effect of sulfated astragalus polysaccharide on cellular infectivity of infectious bursal disease virus. Int J Biol Macromol. 42:166–171. 2008. View Article : Google Scholar

23 

Li Q, Bao JM, Li XL, Zhang T and Shen XH: Inhibiting effect of Astragalus polysaccharides on the functions of CD4+CD25 highTreg cells in the tumor microenvironment of human hepatocellular carcinoma. Chin Med J (Engl). 125:786–793. 2012.

24 

Liu X, Yang Y, Zhang X, Xu S, He S, Huang W and Roberts MS: Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-β/Smad in HepG2 cell. J Gastroenterol Hepatol. 25:420–426. 2010. View Article : Google Scholar

25 

Na D, Liu FN, Miao ZF, Du ZM and Xu HM: Astragalus extract inhibits destruction of gastric cancer cells to mesothelial cells by anti-apoptosis. World J Gastroenterol. 15:570–577. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Zhu ZY, Liu RQ, Si CL, Zhou F, Wang YX, Ding LN, Jing C, Liu AJ and Zhang YM: Structural analysis and anti-tumor activity comparison of polysaccharides from Astragalus. Carbohydr Polym. 85:895–902. 2011. View Article : Google Scholar

27 

Tin MM, Cho CH, Chan K, James AE and Ko JK: Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft. Carcinogenesis. 28:1347–1355. 2007. View Article : Google Scholar

28 

Tian QE, Li HD, Yan M, Cai HL, Tan QY and Zhang WY: Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice. World J Gastroenterol. 18:7079–7086. 2012. View Article : Google Scholar

29 

Zhou L, Zhang N, Song W, You N, Li Q, Sun W, Zhang Y, Wang D and Dou K: The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocellular carcinoma. PLoS One. 8:e573822013. View Article : Google Scholar : PubMed/NCBI

30 

Zhu MS, Xu LB, Zeng H, Shi XD, Wu WR and Liu C: Association of Notch1 with vasculogenic mimicry in human hepatocellular carcinoma cell lines. Int J Clin Exp Pathol. 7:5782–5791. 2014.PubMed/NCBI

31 

Yoshida R, Nagata M, Nakayama H, Niimori-Kita K, Hassan W, Tanaka T, Shinohara M and Ito T: The pathological significance of Notch1 in oral squamous cell carcinoma. Lab Invest. 93:1068–1081. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Roy M, Pear WS and Aster JC: The multifaceted role of Notch in cancer. Curr Opin Genet Dev. 17:52–59. 2007. View Article : Google Scholar

33 

Jiang L, Wu J, Chen Q, Hu X, Li W and Hu G: Notch1 expression is upregulated in glioma and is associated with tumor progression. J Clin Neurosci. 18:387–390. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Wael H, Yoshida R, Kudoh S, Hasegawa K, Niimori-Kita K and Ito T: Notch1 signaling controls cell proliferation, apoptosis and differentiation in lung carcinoma. Lung Cancer. 85:131–140. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Wang M, Wu L, Wang L and Xin X: Down-regulation of Notch1 by gamma-secretase inhibition contributes to cell growth inhibition and apoptosis in ovarian cancer cells A2780. Biochem Biophys Res Commun. 393:144–149. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Wang CL, Meng M, Liu SB, Wang LR, Hou LH and Cao XH: A chemically sulfated polysaccharide from Grifola frondosa induces HepG2 cell apoptosis by notch1-NF-κB pathway. Carbohydr Polym. 95:282–287. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Zhang JX, Han YP, Bai C and Li Q: Notch1/3 and p53/p21 are a potential therapeutic target for APS-induced apoptosis in non-small cell lung carcinoma cell lines. Int J Clin Exp Med. 8:12539–12547, eCollection. 2015.PubMed/NCBI

38 

Yuan CH, Liu YF and Cheng Y: Experimental study on effect of Astragalus extractum on canine isolated kidney during hypothermia perfusion and preservation. Zhongguo Zhong Xi Yi Jie He Za Zhi. 23:291–293. 2003.In Chinese. PubMed/NCBI

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Copy and paste a formatted citation
APA
Huang, W., Liao, W., & Sun, R. (2016). Astragalus polysaccharide induces the apoptosis of human hepatocellular carcinoma cells by decreasing the expression of Notch1. International Journal of Molecular Medicine, 38, 551-557. https://doi.org/10.3892/ijmm.2016.2632
MLA
Huang, W., Liao, W., Sun, R."Astragalus polysaccharide induces the apoptosis of human hepatocellular carcinoma cells by decreasing the expression of Notch1". International Journal of Molecular Medicine 38.2 (2016): 551-557.
Chicago
Huang, W., Liao, W., Sun, R."Astragalus polysaccharide induces the apoptosis of human hepatocellular carcinoma cells by decreasing the expression of Notch1". International Journal of Molecular Medicine 38, no. 2 (2016): 551-557. https://doi.org/10.3892/ijmm.2016.2632