Skip to main content

Advertisement

SpringerLink
Log in

Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches. In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth. However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies. This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05). These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.

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

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BMC:

Biomolecular condensates

BMDCs:

Bone marrow-derived cells

CBD:

Cannabidiol

CNR1:

Cannabinoid receptor 1

CNR2:

Cannabinoid receptor 2

CSCs:

Cancer stem cells

eIF2:

Eukaryotic initiator factor

GBM:

Glioblastoma

IHC:

Immunohistochemistry

p-eIF2:

Phosphorylated eukaryotic initiator factor 2

PPI:

Protein–Protein interaction

SGs:

Stress granules

TIAR-1:

T-cell intracellular antigen related protein

References

  1. Le Rhun E, Preusser M, Roth P, Reardon DA, van den Bent M, Wen P, Reifenberger G, Weller M. Molecular targeted therapy of glioblastoma. Cancer Treat Rev. 2019;80: 101896. https://doi.org/10.1016/j.ctrv.2019.101896.

    Article  CAS  PubMed  Google Scholar 

  2. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374: n1560. https://doi.org/10.1136/bmj.n1560.

    Article  PubMed  Google Scholar 

  3. Khodadadi H, Salles É, Alptekin A, Mehrabian D, Rutkowski M, Arbab AS, Yeudall WA, Yu JC, Morgan JC, Hess DC, et al. Inhalant cannabidiol inhibits glioblastoma progression through regulation of tumor microenvironment. Cannabis Cannabinoid Res. 2023;8:824–34. https://doi.org/10.1089/can.2021.0098.

    Article  CAS  PubMed  Google Scholar 

  4. Jayabalan AK, Adivarahan S, Koppula A, Abraham R, Batish M, Zenklusen D, Griffin DE, Leung AKL. Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity. Proc Natl Acad Sci. 2021. https://doi.org/10.1073/pnas.2021719118.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Swain P, Weber SC. Dissecting the complexity of biomolecular condensates. Biochem Soc Trans. 2020;48:2591–602. https://doi.org/10.1042/BST20200351.

    Article  CAS  PubMed  Google Scholar 

  6. Lyon AS, Peeples WB, Rosen MK. A framework for understanding the functions of biomolecular condensates across scales. Nat Rev Mol Cell Biol. 2021;22:215–35. https://doi.org/10.1038/s41580-020-00303-z.

    Article  CAS  PubMed  Google Scholar 

  7. Hernandez-Candia CN, Pearce S, Tucker CL. A modular tool to query and inducibly disrupt biomolecular condensates. Nat Commun. 2021;12:1809. https://doi.org/10.1038/s41467-021-22096-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Van Treeck B, Protter DSW, Matheny T, Khong A, Link CD, Parker R. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc Natl Acad Sci. 2018;115:2734–9. https://doi.org/10.1073/pnas.1800038115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Choi S, Sa M, Cho N, Kim KK, Park SH. Rbfox2 dissociation from stress suppresses cancer progression. Exp Mol Med. 2019;51:1–12. https://doi.org/10.1038/s12276-019-0246-y.

    Article  CAS  PubMed  Google Scholar 

  10. Song MS, Grabocka E. Stress granules in cancer. Rev Physiol Biochem Pharmacol. 2020. https://doi.org/10.1007/112_2020_37.

    Article  Google Scholar 

  11. Huelgas-Morales G, Silva-Garcia CG, Salinas LS, Greenstein D, Navarro RE. The stress granule RNA-binding protein TIAR-1 protects female germ cells from heat shock in Caenorhabditis elegans. G3. 2016;6:1031–47. https://doi.org/10.1534/g3.115.026815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jeon P, Lee JA. Dr. Jekyll and Mr. Hyde? physiology and pathology of neuronal stress granules. Front Cell Dev Biol. 2021. https://doi.org/10.3389/fcell.2021.609698.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Silva JM, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, Soares-Cunha C, Mazuik BF, Takashima A, Ludovico P, et al. Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. 2019;26:1411–27. https://doi.org/10.1038/s41418-018-0217-1.

    Article  CAS  PubMed  Google Scholar 

  14. Attwood KM, Robichaud A, Westhaver LP, Castle EL, Brandman DM, Balgi AD, Roberge M, Colp P, Croul S, Kim I, et al. Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells. Cell Death Dis. 2020;11:989. https://doi.org/10.1038/s41419-020-03159-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13. https://doi.org/10.1093/nar/gky1131.

    Article  CAS  PubMed  Google Scholar 

  16. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523. https://doi.org/10.1038/s41467-019-09234-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, Lachmann A, Wojciechowicz ML, Kropiwnicki E, Jagodnik KM, et al. Gene set knowledge discovery with Enrichr. Curr Protoc. 2021;1: e90. https://doi.org/10.1002/cpz1.90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hao F, Feng Y. Cannabidiol (CBD) enhanced the hippocampal immune response and autophagy of APP/PS1 alzheimer’s mice uncovered by RNA-seq. Life Sci. 2021;1(264): 118624.

    Article  Google Scholar 

  19. Bian YM, He XB, Jing YK, Wang LR, Wang JM, Xie XQ. Computational systems pharmacology analysis of cannabidiol: a combination of chemogenomics-knowledgebase network analysis and integrated in silico modeling and simulation. Acta Pharmacol Sin. 2019;40(3):374–86.

    Article  CAS  PubMed  Google Scholar 

  20. Carrano A, Juarez JJ, Incontri D, Ibarra A, Guerrero Cazares H. Sex-specific differences in glioblastoma. Cells. 2021;10(7):1783.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Authors are thankful to Mr. Carter Haynes for his invaluable assistance in professional editing and proofreading of this current manuscript. Further, authors thank ThriftMaster Holding Group for providing the inhalant CBD for this study. Authors also thank Medicinal Cannabis of Georgia for providing help in optimizing the CBD dosage.

Funding

This work was supported by institutional seed funding from the Dental College of Georgia at Augusta University.

Author information

Authors and Affiliations

  1. DCG Center for Excellence in Research, Scholarship and Innovation (CERSI), Augusta University, Augusta, GA, USA

    Lei P. Wang, Pablo Shimaoka Chagas, Évila Lopes Salles, Sahar Emami Naeini, Jules Gouron, Hannah M. Rogers, Bidhan Bhandari & Babak Baban

  2. Department of Oral Biology and Diagnostic Sciences, Dental Colleg of Georgia, Augusta University, Augusta, GA, 30912, USA

    Lei P. Wang, Pablo Shimaoka Chagas, Évila Lopes Salles, Sahar Emami Naeini, Jules Gouron, Hannah M. Rogers, Bidhan Bhandari & Babak Baban

  3. Georgia Institute of Cannabis Research, Medicinal Cannabis of Georgia LLC, Augusta, GA, 30912, USA

    Lei P. Wang & Babak Baban

  4. Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, SP, Brazil

    Pablo Shimaoka Chagas

  5. Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Hesam Khodadadi, David C. Hess & Babak Baban

  6. Georgia Cancer Center, Augusta University, Augusta, GA, USA

    Ahmet Alptekin & Ali S. Arbab

  7. Cancer Biology Research Center & Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xu Qin

  8. Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Kumar Vaibhav, Krishnan M. Dhandapani & Martin J. Rutkowski

  9. European Medical Association (EMA), Brussels, Belgium

    Vincenzo Costigliola

  10. Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Jack C. Yu

Authors
  1. Lei P. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pablo Shimaoka Chagas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Évila Lopes Salles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sahar Emami Naeini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jules Gouron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hannah M. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hesam Khodadadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bidhan Bhandari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmet Alptekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kumar Vaibhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vincenzo Costigliola
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. David C. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Krishnan M. Dhandapani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ali S. Arbab
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Martin J. Rutkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jack C. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Babak Baban
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. LPW, JCY, XQ and BB: Study conception and design, analysis and interpretation of data, and drafting the article., PSC, ÉLS, SEN, HK and BBH: Acquisition of data and drafting the article., AA: Culturing and providing the GBM tumor cell line., KV, VC, DCH, KMD ASA, JG and HMR: Editing and Scientific Contribution., MJR: Clinical interpretation and advice and editing.

Corresponding author

Correspondence to Babak Baban.

Ethics declarations

Competing interests

(1) Lei Phillip Wang, Babak Baban, and Jack Yu are members of Medicinal Cannabis of Georgia with no financial interest. (2) All other authors declare no conflict of interest. (3)Thriftmaster Holding Group (THG) is the provider of CBD inhalers and has a licensing contract with Augusta University. (4) THG had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Ethics approval

Animal experiments were approved (protocol # 2011–0062) by the Institutional Animal Care and Use Committee (IACUC) of Augusta University and followed the IACUC guidelines. There was no human subjects/samples used in this study.

Additional information

Publisher's Note

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

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

Wang, L.P., Chagas, P.S., Salles, É.L. et al. Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma. Med Oncol 41, 140 (2024). https://doi.org/10.1007/s12032-024-02381-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-024-02381-x

Keywords

Search

Navigation