SpringerLink
Log in

Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway.

Graphical Abstract

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Data availability

Enquiries about data availability should be directed to the authors.

Abbreviations

DHA:

Dihydroartemisinin

ERRα:

Estrogen-related receptor alpha

TMZ:

Temozolomide

PGC-1α:

Peroxisome proliferator-activated receptor-γ co-activator-1α

ECAR:

extracellular acidification rate

OCR:

oxygen consumption rate

References

  1. Goodenberger ML, Jenkins RB (2012) Genetics of adult glioma. Cancer Genet 205:613–621. https://doi.org/10.1016/j.cancergen.2012.10.009

    Article  PubMed  CAS  Google Scholar 

  2. Walker MD, Strike TA, Sheline GE (1979) An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725–1731. https://doi.org/10.1016/0360-3016(79)90553-4

    Article  PubMed  CAS  Google Scholar 

  3. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198. https://doi.org/10.3171/jns.2001.95.2.0190

    Article  PubMed  CAS  Google Scholar 

  4. Ameratunga M, Pavlakis N, Wheeler H, Grant R, Simes J, Khasraw M (2018) Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst Rev 11:CD008218. https://doi.org/10.1002/14651858.CD008218.pub4

    Article  PubMed  Google Scholar 

  5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G and National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi: https://doi.org/10.1056/NEJMoa043330

  6. Green DR, Llambi F (2015) Cell death signaling. Cold Spring Harb Perspect Biol 7:a006080. https://doi.org/10.1101/cshperspect.a006080

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87:1157–1180. https://doi.org/10.1007/s00204-013-1034-4

    Article  PubMed  CAS  Google Scholar 

  8. Burke PJ (2017) Mitochondria, bioenergetics and apoptosis in cancer. Trends Cancer 3:857–870. https://doi.org/10.1016/j.trecan.2017.10.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Lopez J, Tait SW (2015) Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 112:957–962. https://doi.org/10.1038/bjc.2015.85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. D’Souza GG, Wagle MA, Saxena V, Shah A (2011) Approaches for targeting mitochondria in cancer therapy. Biochim Biophys Acta 1807:689–696. https://doi.org/10.1016/j.bbabio.2010.08.008

    Article  PubMed  CAS  Google Scholar 

  11. Tu Y (1999) The development of new antimalarial drugs: qinghaosu and dihydro-qinghaosu. Chin Med J (Engl) 112:976–977

    PubMed  CAS  Google Scholar 

  12. Mi YJ, Geng GJ, Zou ZZ, Gao J, Luo XY, Liu Y, Li N, Li CL, Chen YQ, Yu XY, Jiang J (2015) Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells. PLoS One 10:e0120426. https://doi.org/10.1371/journal.pone.0120426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Yi YC, Liang R, Chen XY, Fan HN, Chen M, Zhang J, Zhu JS (2021) Dihydroartemisinin suppresses the tumorigenesis and cycle progression of colorectal cancer by targeting CDK1/CCNB1/PLK1 signaling. Front Oncol 11:768879. https://doi.org/10.3389/fonc.2021.768879

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Zhang CZ, Pan Y, Cao Y, Lai PB, Liu L, Chen GG, Yun J (2012) Histone deacetylase inhibitors facilitate dihydroartemisinin-induced apoptosis in liver cancer in vitro and in vivo. PLoS ONE 7:e39870. https://doi.org/10.1371/journal.pone.0039870

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Wang Q, Wu S, Zhao X, Zhao C, Zhao H, Huo L (2015) Mechanisms of dihydroartemisinin and dihydroartemisinin/holotransferrin cytotoxicity in T-cell lymphoma cells. PLoS ONE 10:e0137331. https://doi.org/10.1371/journal.pone.0137331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Jansen FH, Adoubi I, Kouassi Comoe JC, Cnodder TDE, Jansen N, Tschulakow A, Efferth T (2011) First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. Anticancer Res 31:4417–4422

    PubMed  CAS  Google Scholar 

  17. Mao H, Gu H, Qu X, Sun J, Song B, Gao W, Liu J, Shao Q (2013) Involvement of the mitochondrial pathway and Bim/Bcl-2 balance in dihydroartemisinin-induced apoptosis in human breast cancer in vitro. Int J Mol Med 31:213–218. https://doi.org/10.3892/ijmm.2012.1176

    Article  PubMed  CAS  Google Scholar 

  18. Handrick R, Ontikatze T, Bauer KD, Freier F, Rubel A, Durig J, Belka C, Jendrossek V (2010) Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol Cancer Ther 9:2497–2510. https://doi.org/10.1158/1535-7163.MCT-10-0051

    Article  PubMed  CAS  Google Scholar 

  19. Qin G, Zhao C, Zhang L, Liu H, Quan Y, Chai L, Wu S, Wang X, Chen T (2015) Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. Apoptosis 20:1072–1086. https://doi.org/10.1007/s10495-015-1132-2

    Article  PubMed  CAS  Google Scholar 

  20. Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93:884S-890S. https://doi.org/10.3945/ajcn.110.001917

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, Oakeley EJ, Kralli A (2004) The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci U S A 101:6472–6477. https://doi.org/10.1073/pnas.0308686101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Deblois G, St-Pierre J, Giguere V (2013) The PGC-1/ERR signaling axis in cancer. Oncogene 32:3483–3490. https://doi.org/10.1038/onc.2012.529

    Article  PubMed  CAS  Google Scholar 

  23. Zhang L, Zhu Y, Cheng H, Zhang J, Zhu Y, Chen H, Chen L, Qi H, Ren G, Tang J, Zhong M, Hua W, Shi X, Li Q (2019) The increased expression of estrogen-related receptor alpha correlates with Wnt5a and poor prognosis in patients with glioma. Mol Cancer Ther 18:173–184. https://doi.org/10.1158/1535-7163.MCT-17-0782

    Article  PubMed  CAS  Google Scholar 

  24. Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, ** W, Zhang Y (2013) MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res 73:6046–6055. https://doi.org/10.1158/0008-5472.CAN-13-0358

    Article  PubMed  CAS  Google Scholar 

  25. Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P (2014) Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis 5:e1145. https://doi.org/10.1038/cddis.2014.111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zhao Z, Ji M, Wang Q, He N, Li Y (2020) miR-16-5p/PDK4-mediated metabolic reprogramming is involved in chemoresistance of cervical cancer. Mol Ther Oncolytics 17:509–517. https://doi.org/10.1016/j.omto.2020.05.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Gao Z, Wang T, Li R, Du Y, Lv H, Zhang L, Chen H, Shi X, Li Q, Shen J (2022) The discovery of a novel series of potential ERRalpha inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer in vivo. J Enzyme Inhib Med Chem 37:125–134. https://doi.org/10.1080/14756366.2021.1995728

    Article  PubMed  CAS  Google Scholar 

  28. Zhang L, Liu P, Chen H, Li Q, Chen L, Qi H, Shi X, Du Y (2016) Characterization of a selective inverse agonist for estrogen related receptor alpha as a potential agent for breast cancer. Eur J Pharmacol 789:439–448. https://doi.org/10.1016/j.ejphar.2016.08.008

    Article  PubMed  CAS  Google Scholar 

  29. Bost F, Kaminski L (2019) The metabolic modulator PGC-1alpha in cancer. Am J Cancer Res 9:198–211

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622. https://doi.org/10.1172/JCI27794

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lee SY (2016) Temozolomide resistance in glioblastoma multiforme. Genes Dis 3:198–210. https://doi.org/10.1016/j.gendis.2016.04.007

    Article  PubMed  PubMed Central  Google Scholar 

  32. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  33. Qu C, Ma J, Liu X, Xue Y, Zheng J, Liu L, Liu J, Li Z, Zhang L, Liu Y (2017) Dihydroartemisinin exerts anti-tumor activity by inducing mitochondrion and endoplasmic reticulum apoptosis and autophagic cell death in human glioblastoma cells. Front Cell Neurosci 11:310. https://doi.org/10.3389/fncel.2017.00310

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Xu CH, Liu Y, **ao LM, Guo CG, Zheng SY, Zeng EM, Li DH (2017) Dihydroartemisinin treatment exhibits antitumor effects in glioma cells through induction of apoptosis. Mol Med Rep 16:9528–9532. https://doi.org/10.3892/mmr.2017.7832

    Article  PubMed  CAS  Google Scholar 

  35. Schulze A, Harris AL (2012) How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491:364–373. https://doi.org/10.1038/nature11706

    Article  PubMed  CAS  Google Scholar 

  36. Bhardwaj V, He J (2020) Reactive oxygen species, metabolic plasticity, and drug resistance in cancer. Int J Mol Sci 21:3412. https://doi.org/10.3390/ijms21103412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Zong WX, Rabinowitz JD, White E (2016) Mitochondria and cancer. Mol Cell 61:667–676. https://doi.org/10.1016/j.molcel.2016.02.011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Debatin KM, Poncet D, Kroemer G (2002) Chemotherapy: targeting the mitochondrial cell death pathway. Oncogene 21:8786–8803. https://doi.org/10.1038/sj.onc.1206039

    Article  PubMed  CAS  Google Scholar 

  39. Adrain C, Martin SJ (2001) The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390–397. https://doi.org/10.1016/s0968-0004(01)01844-8

    Article  PubMed  CAS  Google Scholar 

  40. Villena JA, Kralli A (2008) ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol Metab 19:269–276. https://doi.org/10.1016/j.tem.2008.07.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Giguere V (2008) Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev 29:677–696. https://doi.org/10.1210/er.2008-0017

    Article  PubMed  CAS  Google Scholar 

  42. Laganiere J, Tremblay GB, Dufour CR, Giroux S, Rousseau F, Giguere V (2004) A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression. J Biol Chem 279:18504–18510. https://doi.org/10.1074/jbc.M313543200

    Article  PubMed  CAS  Google Scholar 

  43. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370. https://doi.org/10.1016/j.cmet.2005.05.004

    Article  PubMed  CAS  Google Scholar 

  44. Charest-Marcotte A, Dufour CR, Wilson BJ, Tremblay AM, Eichner LJ, Arlow DH, Mootha VK, Giguere V (2010) The homeobox protein Prox1 is a negative modulator of ERR{alpha}/PGC-1{alpha} bioenergetic functions. Genes Dev 24:537–542. https://doi.org/10.1101/gad.1871610

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Cai Q, Lin T, Kamarajugadda S, Lu J (2013) Regulation of glycolysis and the Warburg effect by estrogen-related receptors. Oncogene 32:2079–2086. https://doi.org/10.1038/onc.2012.221

    Article  PubMed  CAS  Google Scholar 

  46. Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, Puigserver P (2013) PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23:287–301. https://doi.org/10.1016/j.ccr.2012.11.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850. https://doi.org/10.1001/jama.2013.280319

    Article  PubMed  CAS  Google Scholar 

  48. Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD, Hoshyar R, Seyfoori A, Sepehri Z, Ande SR, Khadem F, Akbari M, Gorman AM, Samali A, Klonisch T, Ghavami S (2018) Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184:13–41. https://doi.org/10.1016/j.pharmthera.2017.10.017

    Article  PubMed  CAS  Google Scholar 

  49. Chen T, Li M, Zhang R, Wang H (2009) Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med 13:1358–1370. https://doi.org/10.1111/j.1582-4934.2008.00360.x

    Article  PubMed  CAS  Google Scholar 

  50. Zhou HJ, Zhang JL, Li A, Wang Z, Lou XE (2010) Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas in vivo and inhibits murine Lewis lung carcinoma cell line growth in vitro. Cancer Chemother Pharmacol 66:21–29. https://doi.org/10.1007/s00280-009-1129-z

    Article  PubMed  CAS  Google Scholar 

  51. Wu GS, Lu JJ, Guo JJ, Huang MQ, Gan L, Chen XP, Wang YT (2013) Synergistic anti-cancer activity of the combination of dihydroartemisinin and doxorubicin in breast cancer cells. Pharmacol Rep 65:453–459. https://doi.org/10.1016/s1734-1140(13)71021-1

    Article  PubMed  CAS  Google Scholar 

  52. Davis TM, Binh TQ, Ilett KF, Batty KT, Phuong HL, Chiswell GM, Phuong VD, Agus C (2003) Penetration of dihydroartemisinin into cerebrospinal fluid after administration of intravenous artesunate in severe falciparum malaria. Antimicrob Agents Chemother 47:368–370. https://doi.org/10.1128/AAC.47.1.368-370.2003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by the National Natural Science Foundation of China (81901399, 81973399), the Shanghai ‘Rising Stars of Medical Talent’ Youth Development Program (Youth Medical Talents-Clinical Pharmacist Program), Shanghai Key Clinical Specialty Projects-Clinical Pharmacy (shslczdzk06502), and Scientific Research Project of Shanghai Health and Family Planning Commission to (20184Y0194, 20204Y0445).

Funding

Scientific Research Project of Shanghai Health and Family Planning Commission, 20184Y0194,20204Y0445, National Natural Science Foundation of China, 81901399, 81973399.

Author information

Author notes

  1. Wenxin Zhang and Yan Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Huashan Hospital, Fudan University, No. 12 Urumqi Middle Road, Shanghai, 200040, People’s Republic of China

    Wenxin Zhang, Yan Wang, Lu Chen, Haifei Chen, Huijie Qi, Liudi Zhang, Tianxiao Wang & Qunyi Li

  2. School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), **an, People’s Republic of China

    Yong Zheng & Yongli Du

Authors
  1. Wenxin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haifei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huijie Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongli Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Liudi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tianxiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qunyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Wenxin Zhang: Conceptualization, Formal analysis, Data curation Yan Wang: Conceptualization, Formal analysis, Data curation. Lu Chen: Visualization, Investigation. Haifei Chen: Data curation, Formal analysis. Huijie Qi: Resources, Data curation. Yong Zheng: Data curation, Formal analysis. Yongli Du: Data curation, Formal analysis. Liudi Zhang: Investigation, Formal analysis. Tianxiao Wang: Conceptualization, Data curation, Visualization, Investigation, Supervision, Writing–original draft. Qunyi Li: Visualization, Supervision, Writing – original draft. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring intergrity and accuracy.

Corresponding authors

Correspondence to Liudi Zhang, Tianxiao Wang or Qunyi Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 390 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Wang, Y., Chen, L. et al. Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04892-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-023-04892-z

Keywords

Search

Navigation