Skip to main content
SpringerLink
Log in

Salvianolic acid B suppresses EMT and apoptosis to lessen drug resistance through AKT/mTOR in gastric cancer cells

  • Original Article
  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

The drug resistance of tumor cells greatly reduces the efficacy of chemotherapy drugs in gastric cancer. Salvianolic acid B (Sal-B) is considered as a chemopreventive agent which suppresses oxidative stress and apoptosis. Therefore, the study aims to clarify the mechanism of Sal-B in drug-resistant gastric cancer cells. CCK8 assay analyzed cell viabilities after GES1, AGS and AGS/DDP cells were respectively treated by Sal-B of different concentration or after AGS/DDP cells were disposed by cisplatin (DDP) in different concentration. The colony formation, ROS generation, apoptosis, migration, invasion and EMT marker proteins were respectively analyzed through formation assay, ROS kits, TUNNEL staining, Wound healing, Transwell assays and Western blot. The results demonstrated that Sal-B acted alone or in synergy with DDP to reduce cell viabilities, initiate ROS generation, promote cell apoptosis, as well as decrease migration, invasion and EMT in AGS and AGS/DDP cells. AKT activator and mTOR activator significantly reversed the above effects of Sal-B. Collectively, Sal-B regulated proliferation, EMT and apoptosis to reduce the resistance to DDP via AKT/mTOR pathway in DDP-resistant gastric cancer cells. Sal-B could be a potential anti-drug resistance agent to chemotherapy in gastric cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464

    Article  CAS  Google Scholar 

  • Arima Y, Inoue Y, Shibata T, Hayashi H, Nagano O, Saya H, Taya Y (2008) Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res 68:5104–5112

    Article  CAS  Google Scholar 

  • Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J (2012) E-cadherin dysfunction in gastric cancer—cellular consequences, clinical applications and open question. FEBS Lett 586:2981

    Article  CAS  Google Scholar 

  • Cui X-L, Li K-J, Ren H-X, Zhang Y-J, X-D Liu (2019) Extract of Cycas revoluta Thunb. enhances the inhibitory effect of 5-fluorouracil on gastric cancer cells through the AKT-mTOR pathway. World J Gastroenterol 25:1854

    Article  CAS  Google Scholar 

  • Du Y, Zhu M, Zhou X, Huang Z, Zhu J, Xu J, Cheng G, Shu Y, Liu P, Zhu W, Wang T (2016) miR-20a enhances cisplatin resistance of human gastric cancer cell line by targeting NFKBIB. Tumor Biol 37:1261–1269

    Article  CAS  Google Scholar 

  • Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, Rocchi S, Mallavialle A, Galibert MD, Khammari A, Lacour JP, Ballotti R, Deckert M, Tartare-Deckert S (2012) The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS ONE 7:e40378

    Article  CAS  Google Scholar 

  • Gao S, Li S, Li Q, Zhang F, Sun M, Wan Z, Wang S (2019) Protective effects of salvianolic acid B against hydrogen peroxideinduced apoptosis of human umbilical vein endothelial cells and underlying mechanisms. Int J Mol Med 44:457

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gong L, Di C, Xia X, Wang J, Chen G, Shi J, Chen P, Xu H, Zhang W (2016) AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells. Int J Oncol 49:2538

    Article  CAS  Google Scholar 

  • Guo P, Wang J, Gao W, Xia L, Wu S, Wan B, Lei X, Li Y (2018) Salvianolic acid B reverses multidrug resistance in nude mice bearing human colon cancer stem cells. Mol Med Rep 18:1323–1334

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang D, Duan H, Huang H, Tong X, Han Y, Ru G, Qu L, Shou C, Zhao Z (2016) Cisplatin resistance in gastric cancer cells is associated with HER2 upregulation-induced epithelial-mesenchymal transition. Sci Rep 6:20502

    Article  CAS  Google Scholar 

  • Iwatsuki M, Mimori K, Fukagawa T, Ishii H, Yokobori T, Sasako M, Baba H, Mori M (2010) The clinical significance of vimentin-expressing gastric cancer cells in bone marrow. Ann Surg Oncol 17:2526–2533

    Article  Google Scholar 

  • Jiang C, Ma Z, Zhang G, Yang X, Du Q, Wang W (2019) CSNK2A1 promotes gastric cancer invasion through the PI3K-Akt-mTOR signaling pathway. Cancer Manag Res 11:10135–10143

    Article  CAS  Google Scholar 

  • Jing Z, Fei W, Zhou J, Zhang L, Chen L, Zhang X, Liang X, Xie J, Fang Y, Sui X, Han W, Pan H (2016) Salvianolic acid B, a novel autophagy inducer, exerts antitumor activity as a single agent in colorectal cancer cells. Oncotarget 7:61509–61519

    Article  Google Scholar 

  • Katary MA, Abdelsayed R, Alhashim A, Abdelhasib M, Elmarakby AA (2019) Salvianolic Acid B slows the progression of breast cancer cell growth via enhancement of apoptosis and reduction of oxidative stress, inflammation, and angiogenesis. Int J Mol Sci 20:5653

    Article  CAS  Google Scholar 

  • Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discovery 8:627–644

    Article  CAS  Google Scholar 

  • Liu Z, Yan Y, Cao S, Chen Y (2018) Long non-coding RNA SNHG14 contributes to gastric cancer development through targeting miR-145/SOX9 axis. J Cell Biochem 119:6905–6913

    Article  CAS  Google Scholar 

  • Roy R, Singh SK, Chauhan LK, Das M, Tripathi A, Dwivedi PD (2014) Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition. Toxicol Lett 227:29–40

    Article  CAS  Google Scholar 

  • Soltani A, Bahreyni A, Boroumand N, Roshan MK, Khazaei M, Ryzhikov M, Soleimanpour S, Avan A, Hassanian SM (2018) Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives. J Cell Physiol 233:4783–4790

    Article  CAS  Google Scholar 

  • Sun XP, Dong X, Lin L, Jiang X, Wei Z, Zhai B, Sun B, Zhang Q, Wang X, Jiang H (2014) Up-regulation of survivin by AKT and hypoxia-inducible factor?1α contributes to cisplatin resistance in gastric cancer. FEBS J 281:115–128

    Article  CAS  Google Scholar 

  • Thiery JP (2002) Epithelial? Mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442

    Article  CAS  Google Scholar 

  • Vanhaesebroeck B, Vogt PK, Rommel C (2010) PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 347:1–19

    PubMed  Google Scholar 

  • Voon D, Huang R, Jackson R, Thiery J (2017) The EMT spectrum and therapeutic opportunities. Mol Oncol 11:878

    Article  Google Scholar 

  • Wang M, Sun G, Wu P, Chen R, Yao F, Qin M, Luo Y, Sun H, Zhang Q, Dong X, Sun X (2013) Salvianolic Acid B prevents arsenic trioxide-induced cardiotoxicity in vivo and enhances its anticancer activity in vitro. Evid Based Complement Altern Med 2013:759483

    Google Scholar 

  • Wang Z, Tang T, Wang S, Cai T, Tao H, Zhang Q, Qi S, Qi Z (2020) Aloin inhibits the proliferation and migration of gastric cancer cells by regulating NOX2-ROS-mediated pro-survival signal pathways. Drug Des Devel Ther 14:145–155

    Article  CAS  Google Scholar 

  • Wu ZH, Lin C, Liu CC, Jiang WW, Huang MZ, Liu X, Guo WJ (2018) MiR-616-3p promotes angiogenesis and EMT in gastric cancer via the PTEN/AKT/mTOR pathway. Biochem Biophys Res Commun 501:1068–1073

    Article  CAS  Google Scholar 

  • Xia C, Zeng H, Zheng Y (2020) Low–intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS–miR–21–PTEN axis. Mol Med Rep 21:989–998

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xue D, Pan ST, Zhou X, Ye F, Zhou Q, Shi F, He F, Yu H, Qiu J (2020) Plumbagin enhances the anticancer efficacy of cisplatin by increasing intracellular ROS in human tongue squamous cell carcinoma. Oxid Med Cell Longev 2020:5649174

    PubMed  PubMed Central  Google Scholar 

  • Yao Y, Zhou D, Shi D, Zhang H, Zhan S, Shao X, Sun K, Sun L, Wu G, Tian K, Zhu X (2019) GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKT-mTOR pathway. Biomed Pharmacother 111:993

    Article  CAS  Google Scholar 

  • Yu X, Guan Q, Wang Y, Shen H, Zhai L, Lu X, Jin Y (2019) Anticonvulsant and anti-apoptosis effects of salvianolic acid B on pentylenetetrazole-kindled rats via AKT/CREB/BDNF signaling. Epilepsy Res 154:90–96

    Article  CAS  Google Scholar 

  • Zeng L, Liao Q, Zou Z, Wen Y, Wang J, Liu C, He Q, Weng N, Zeng J, Tang H (2018) Long non-coding RNA XLOC_006753 promotes the development of multidrug resistance in gastric cancer cells through the PI3K/AKT/mTOR signaling pathway. Cell Physiol Biochem 51:1221–1236

    Article  CAS  Google Scholar 

  • Zhang D, Fan D (2007) Multidrug resistance in gastric cancer: recent research advances and ongoing therapeutic challenges. Expert Rev Anticancer Ther 7:1369–1378

    Article  CAS  Google Scholar 

  • Zhang D, Fan D (2010) New insights into the mechanisms of gastric cancer multidrug resistance and future perspectives. Fut Oncol 6:527–537

    Article  CAS  Google Scholar 

  • Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, Xu P, Sun G, Xu J, Lv J, Xu Z (2019) Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer 18:20

    Article  Google Scholar 

  • Zhao Y, Guo Y, Gu X (2011) Salvianolic acid B, a potential chemopreventive agent, for head and neck squamous cell cancer. J Oncol 2011:534548

    Article  Google Scholar 

  • Zheng P, Chen L, Yuan X, Luo Q, Liu Y, Xie G, Ma Y, Shen L (2017) Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res 36:53

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Traditional Chinese Medicine, Affiliated Hospital of Beihua University, Jilin, 132000, China

    Jie Wang

  2. Gastroenterology Department, Affiliated Hospital of Beihua University, Jilin, 132000, China

    Yingze Ma & Xiaohui Guan

  3. Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Min Guo

  4. Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Haixia Yang No. 157 West Five Road, Xi’an, 710004, Shaanxi, China

    Haixia Yang

Authors
  1. Jie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingze Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haixia Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaohui Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haixia Yang.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Ma, Y., Guo, M. et al. Salvianolic acid B suppresses EMT and apoptosis to lessen drug resistance through AKT/mTOR in gastric cancer cells. Cytotechnology 73, 49–61 (2021). https://doi.org/10.1007/s10616-020-00441-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-020-00441-4

Keywords

Search

Navigation