Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rg1 Induces Autophagy in Colorectal Cancer through Inhibition of the Akt/mTOR/p70S6K Pathway

  • Ruiqi Liu (Jiangsu Province Academy of Traditional Chinese Medicine) ;
  • Bin Zhang (Nanjing Lishui District Hospital of Traditional Chinese Medicine) ;
  • Shuting Zou (Jiangsu Province Academy of Traditional Chinese Medicine) ;
  • Li Cui (Jiangsu Province Academy of Traditional Chinese Medicine) ;
  • Lin, Lin (Gastroenterology, Shenzhen Hospital of Guangzhou University of Chinese Medicine) ;
  • Lingchang Li (Jiangsu Province Academy of Traditional Chinese Medicine)
  • Received : 2023.10.27
  • Accepted : 2023.12.29
  • Published : 2024.04.28
Download PDF
⟨ Previous Next ⟩

Abstract

This study aimed to elucidate the anti-colon cancer mechanism of ginsenoside Rg1 in vitro and in vivo. Cell viability rate was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tetrazolium assay. The inhibitory effect of ginsenoside Rg1 against CT26 cell proliferation gradually increased with increasing concentration. The in vivo experiments also demonstrated an antitumor effect. The monodansylcadaverine (MDC), transmission electron microscopy (TEM), and expression of autophagy marker proteins confirmed that ginsenoside Rg1 induced autophagy in vitro. Ginsenoside Rg1 induced autophagy death of CT26 cells, but this effect could be diminished by autophagy inhibitor (3-methyladenine, 3-MA). Additionally, in a xenograft model, immunohistochemical analysis of tumor tissues showed that the LC3 and Beclin-1 proteins were highly expressed in the tumors from the ginsenoside Rg1-treated nude mice, confirming that ginsenoside Rg1 also induced autophagy in vivo. Furthermoer, both in vivo and in vitro, the protein expressions of p-Akt, p-mTOR, and p-p70S6K were inhibited by ginsenoside Rg1, which was verified by Akt inhibitors. These results indicated that the mechanism of ginsenoside Rg1 against colon cancer was associated with autophagy through inhibition of the Akt/mTOR/p70S6K signaling pathway.

Keywords

Acknowledgement

This work was supported by the General Project of the National Clinical Research Base of Traditional Chinese Medicine(JD2019SZXYB04), the third batch of famous doctor reserve talents of Jiangsu Hospital of Integrated Traditional Chinese and Western Medicine, Su Traditional Chinese and Western medicine 2020-11(00051082), and the Scientific Research Project of Jiangsu Provincial Health Commission (M2021047).

References

  1. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. 2019. Colorectal cancer. Lancet 394: 1467-1480. https://doi.org/10.1016/S0140-6736(19)32319-0
  2. Yu T, Yang Y, Kwak YS, Song GG, Kim MY, Rhee MH, et al. 2017. Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2. J. Ginseng Res. 41: 127-133. https://doi.org/10.1016/j.jgr.2016.02.001
  3. Jin S, Jeon JH, Lee S, Kang WY, Seong SJ, Yoon YR, et al. 2019. Detection of 13 ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, compound K, 20(S)-protopanaxadiol, and 20(S)-protopanaxatriol) in human plasma and application of the analytical method to human pharmacokinetic studies following two week-repeated administration of red ginseng extract. Molecules 24: 2618.
  4. Gao Y, Li J, Wang J, Li X, Li J, Chu S, et al. 2020. Ginsenoside Rg1 prevent and treat inflammatory diseases: a review. Int. Immunopharmacol. 87: 106805.
  5. Li L, Wang Y, Qi B, Yuan D, Dong S, Guo D, et al. 2014. Suppression of PMA-induced tumor cell invasion and migration by ginsenoside Rg1 via the inhibition of NF-kappaB-dependent MMP-9 expression. Oncol. Rep. 32: 1779-1786. https://doi.org/10.3892/or.2014.3422
  6. Li W, Li G, She W, Hu X, Wu X. 2019. Targeted antitumor activity of Ginsenoside (Rg1) in paclitaxel-resistant human nasopharyngeal cancer cells are mediated through activation of autophagic cell death, cell apoptosis, endogenous ROS production, S phase cell cycle arrest and inhibition of m-TOR/PI3K/AKT signalling pathway. J. BUON 24: 2056-2061.
  7. Lee SY. 2020. Ginsenoside Rg1 drives stimulations of timosapon in AIII-induced anticancer effects in human osteosarcoma cells. Evid. Based Complement. Alternat. Med. 2020: 8980124.
  8. Wen X, Klionsky DJ. 2020. At a glance: a history of autophagy and cancer. Semin. Cancer Biol. 66: 3-11. https://doi.org/10.1016/j.semcancer.2019.11.005
  9. Aoki M, Fujishita T. 2017. Oncogenic roles of the PI3K/AKT/mTOR axis. Curr. Top. Microbiol. Immunol. 407: 153-189. https://doi.org/10.1007/82_2017_6
  10. Xiang H, Zhang J, Lin C, Zhang L, Liu B, Ouyang L. 2020. Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm. Sin B 10: 569-581. https://doi.org/10.1016/j.apsb.2019.10.003
  11. Mitra S, Lami MS, Ghosh A, Das R, Tallei TE, Fatimawali, et al. 2022. Hormonal therapy for gynecological cancers: how far has science progressed toward clinical applications? Cancers (Basel) 14: 759.
  12. Li X, Liu W, Geng C, Li T, Li Y, Guo Y, et al. 2021. Ginsenoside Rg3 suppresses epithelial-mesenchymal transition via downregulating notch-hes1 signaling in colon cancer cells. Am. J. Chin. Med. 49: 217-235. https://doi.org/10.1142/S0192415X21500129
  13. Wu Q, Deng J, Fan D, Duan Z, Zhu C, Fu R, et al. 2018. Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells. Biochem. Pharmacol. 148: 64-74. https://doi.org/10.1016/j.bcp.2017.12.004
  14. Zhao YG, Codogno P, Zhang H. 2021. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat. Rev. Mol. Cell Biol. 22: 733-750. https://doi.org/10.1038/s41580-021-00392-4
  15. Sun R, Zhai R, Ma C, Miao W. 2020. Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway. Cancer Med. 9: 1141-1151. https://doi.org/10.1002/cam4.2723
  16. Wang Q, Liu Z, Du K, Liang M, Zhu X, Yu Z, et al. 2019. Babaodan inhibits cell growth by inducing autophagy through the PI3K/ AKT/mTOR pathway and enhances antitumor effects of cisplatin in NSCLC cells. Am. J. Transl. Res. 11: 5272-5283.
  17. Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, et al. 2018. Dual role of autophagy in hallmarks of cancer. Oncogene 37: 1142-1158. https://doi.org/10.1038/s41388-017-0046-6
  18. Alzahrani AS. 2019. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin. Cancer Biol. 59: 125-132. https://doi.org/10.1016/j.semcancer.2019.07.009
  19. Li H, Zhao S, Shen L, Wang P, Liu S, Ma Y, et al. 2021. E2F2 inhibition induces autophagy via the PI3K/Akt/mTOR pathway in gastric cancer. Aging (Albany NY) 13: 13626-13643. https://doi.org/10.18632/aging.202891
  20. Hong P, Liu QW, Xie Y, Zhang QH, Liao L, He QY, et al. 2020. Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis. Cell Death Dis. 11: 524.
  21. Sun Z, Zheng L, Liu X, Xing W, Liu X. 2018. Sinomenine inhibits the growth of melanoma by enhancement of autophagy via PI3K/ AKT/mTOR inhibition. Drug Des. Devel. Ther. 12: 2413-2421. https://doi.org/10.2147/DDDT.S155798
  22. Wang J, Li L, Wang J, Song L, Tan N, Wang Z. 2019. Natural naphthohydroquinone dimer rubioncolin c exerts anti-tumor activity by inducing apoptotic and autophagic cell death and inhibiting the NF-kappaB and Akt/mTOR/P70S6K pathway in human cancer cells. Cells 8: 1593.
  23. Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, et al. 2011. Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy 7: 176-187. https://doi.org/10.4161/auto.7.2.14074
  24. Sui Y, Yao H, Li S, Jin L, Shi P, Li Z, et al. 2017. Delicaflavone induces autophagic cell death in lung cancer via Akt/mTOR/p70S6K signaling pathway. J. Mol. Med. (Berl) 95: 311-322. https://doi.org/10.1007/s00109-016-1487-z