Skip to main content

Advertisement

SpringerLink
Log in

The interplay between autophagy and apoptosis induced by tanshinone IIA in prostate cancer cells

  • Original Article
  • Published:
Tumor Biology

Abstract

Tanshinone IIA (T2A), a derivative of phenanthrenequinone and also the major active ingredient of Danshen, has been paid extensive attention as a promising cancer therapy for its potential anti-cancer activities. In this study, the apoptosis and autophagy of human prostate cancer PC-3 cells were observed after 5 μM T2A treatment, as well as their relevance. Mitochondrial-dependent apoptosis was firstly detected through morphological observation and biochemical analysis. Meanwhile, 5 μM T2A successfully triggered the autophagy of PC-3 cells, indicated by increased expression of Beclin1, and LC3 II. Validation experiments were conducted to further consolidate T2A’s contribution to autophagy: Pretreatment with autophagy inhibitor 3-methyladenine (3-MA) provided protection against autophagy and enhanced T2A-induced apoptosis. Besides, the apoptosis suppressor z-VAD-fmk failed to facilitate the formation of autophagic vacuoles, which also proved the T2A-induced autophagy independent of apoptosis. Moreover, the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) efficiently inhibited the expression of Beclin1, LC3-II, and cleaved caspase-3, which indicated apoptosis and autophagy with dependence on intracellular ROS production. Taken together, these results demonstrated that autophagy is the cytoprotective mechanism in this experimental system, and the ROS resulted from T2A treatment played a critical role in apoptosis and autophagy initiation.

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

Similar content being viewed by others

References

  1. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 2012;45:487–98.

    Article  CAS  PubMed  Google Scholar 

  2. Douglas H, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  Google Scholar 

  3. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15:81–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bialik S, Zalckvar E, Ber Y, Rubinstein AD, Kimchi A. Systems biology analysis of programmed cell death. Trends Biochem Sci. 2010;35:556–64.

    Article  CAS  PubMed  Google Scholar 

  5. Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in cancer. Cancer. 1998;83:777–82.

    Article  CAS  PubMed  Google Scholar 

  6. Fu J, Huang H, Liu J, Pi R, Chen J, Liu P. Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis. Eur J Pharmacol. 2007;568:213–21.

    Article  CAS  PubMed  Google Scholar 

  7. Li X, Xu X, Wang J, Yu H, Wang X, Yang H, et al. A system-level investigation into the mechanisms of Chinese Traditional Medicine: Compound Danshen Formula for cardiovascular disease treatment. PLoS One. 2012;7:e43918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang X, Wei Y, Yuan S, Liu G, Lu Y, Zhang J, et al. Potential anticancer activity of tanshinone IIA against human breast cancer. Int J Cancer. 2005;116:799–807.

    Article  CAS  PubMed  Google Scholar 

  9. Li G, Shan C, Liu L, Zhou T, Zhou J, Hu X, et al. Tanshinone IIA inhibits HIF-1alpha and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PLoS One. 2015;10:e0117440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yoon Y, Kim YO, Jeon WK, Park HJ, Sung HJ. Tanshinone IIA isolated from Salvia miltiorrhiza BUNGE induced apoptosis in HL60 human premyelocytic leukemia cell line. J Ethnopharmacol. 1999;68:121–7.

    Article  CAS  PubMed  Google Scholar 

  11. Yuan SL, Wei YQ, Wang XJ, Xiao F, Li SF, Zhang J. Growth inhibition and apoptosis induction of tanshinone II-A on human hepatocellular carcinoma cells. World J Gastroenterol. 2004;10:2024–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma H, Fan Q, Yu J, Xin J, Zhang C. Novel microemulsion of tanshinone IIA, isolated from Salvia miltiorrhiza Bunge, exerts anticancer activity through inducing apoptosis in hepatoma cells. Am J Chin Med. 2013;41:197–210.

    Article  CAS  PubMed  Google Scholar 

  13. Su CC, Chiu TL. Tanshinone IIA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Int J Mol Med. 2010;25:213–6.

    Google Scholar 

  14. Won SH, Lee HJ, Jeong SJ, Lee HJ, Lee EO, Jung DB, et al. Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull. 2010;33:1828–34.

    Article  CAS  PubMed  Google Scholar 

  15. Su CC, Chen GW, Kang JC, Chan MH. Growth inhibition and apoptosis induction by tanshinone IIA in human colon adenocarcinoma cells. Planta Med. 2008;74:1357–62.

    Article  CAS  PubMed  Google Scholar 

  16. Chiu SC, Huang SY, Chang SF, Chen SP, Chen CC, Lin TH, et al. Potential therapeutic roles of tanshinone IIA in human bladder cancer cells. Int J Mol Sci. 2014;15:15622–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Denmeade SR, Lin XS, Isaacs JT. Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate. 1996;28:251–65.

    Article  CAS  PubMed  Google Scholar 

  18. Yun SM, Jung JH, Jeong SJ, Sohn EJ, Kim B, Kim SH. Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytother Res. 2014;PTR 28:458–64.

    Article  CAS  PubMed  Google Scholar 

  19. Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC. Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 2003;63:1311–6.

    CAS  PubMed  Google Scholar 

  20. Tanida I, Ueno T, Kominami E (2008) LC3 and Autophagy. in Autophagosome and Phagosome, Springer. pp 77–88

  21. Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization. Autophagy. 2007;3:323–8.

    Article  CAS  PubMed  Google Scholar 

  22. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.

    Article  CAS  PubMed  Google Scholar 

  23. Boon H, Wong J. Botanical medicine and cancer: a review of the safety and efficacy. Expert Opin Pharmacother. 2004;5:2485–501.

    Article  PubMed  Google Scholar 

  24. Verhoef MJ, Balneaves LG, Boon HS, Vroegindewey A. Reasons for and characteristics associated with complementary and alternative medicine use among adult cancer patients: a systematic review. Integr Cancer Ther. 2005;4:274–86.

    Article  PubMed  Google Scholar 

  25. Chen AJ, Zhang JY, Li CH, Chen XF, Hu ZD, Chen XG. Separation and determination of active components in Radix Salviae miltiorrhizae and its medicinal preparations by nonaqueous capillary electrophoresis. J Sep Sci. 2004;27:569–75.

    Article  CAS  PubMed  Google Scholar 

  26. Galluzzi L, Vitale I, Abrams J, Alnemri E, Baehrecke E, Blagosklonny M, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–20.

    Article  CAS  PubMed  Google Scholar 

  27. Tan ML, Ooi JP, Ismail N, Moad AIH, Muhammad TST. Programmed cell death pathways and current antitumor targets. Pharm Res. 2009;26:1547–60.

    Article  CAS  PubMed  Google Scholar 

  28. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Galluzzi L, Kepp O, Kroemer G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol. 2012;13:780–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Urological Department, Affiliate Hospital of Weifang Medical University, No.2428 Yuhe Road, Weifang, Shandong, China

    Chunlong Li, Xiancheng Han, Hong Zhang, Jinsheng Wu & Bao Li

Authors
  1. Chunlong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiancheng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinsheng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chunlong Li.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Han, X., Zhang, H. et al. The interplay between autophagy and apoptosis induced by tanshinone IIA in prostate cancer cells. Tumor Biol. 37, 7667–7674 (2016). https://doi.org/10.1007/s13277-015-4602-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4602-9

Keywords

Search

Navigation