Skip to main content

Advertisement

SpringerLink
Log in

Connexin 30 mediated rewiring of glucose metabolism in rat C6 xenograft and grades of glioma

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

Abstract

Connexin 30 (Cx30), a tumour-suppressive gap junctional protein, impacts on insulin-like growth factor receptor 1-mediated progression and stemness of glioma. Of late, metabolic reprogramming, a recently adjudged hall mark of malignancy, could reasonably associated with the changes in gap junctional communication in glioma. This newly recognized hallmark of reprogramming of metabolism to maintain the rapid proliferation necessitates further probing to establish the stronger hall marks. Hence, the current study attempted to link the association between the expression of Cx30 with glucose uptake and glucose metabolism in glioma. We have transfected Cx30 in C6 glioma cells, characterized by a low level of intercellular communication and developed xenografts to study the status of glucose transporters (GLUTs), hexokinase 2 and Pyruvate dehydrogenase kinase 1 (PDK 1) along with human glioma tissues by RT-PCR and immunoblotting. The results showed a significant increase in the levels of GLUTs, hexokinase 2 and PDK 1 in C6-implanted rat xenografts and high grades compared to their respective controls, whereas Cx30-transfected C6-implanted rat xenograft and low grades show no significant change compared to that of controls supporting the association between Gap junctional communications and glucose metabolism. We strongly speculate the impact of Cx30 over the glucose metabolism that might provide therapeutic prospects and challenges for anti-glycolytic cancer therapy.

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

Abbreviations

GJIC:

Gap junctional communications

IGF1R:

Insulin-like growth factor receptor 1

GLUTs:

Glucose transporters

Cx:

Connexin

PDK1:

Pyruvate dehydrogenase kinase 1

HK2:

Hexokinase 2

TBS-T:

Tris-based saline Tween 20

WHO:

World Health Organization

LG:

Low grade

HG:

High grade

References

  1. Lin J, Xia L, Liang J, Han Y, Wang H, Oyang L, Tang Y (2019) The roles of glucose metabolic reprogramming in chemo-and radio-resistance. J Exp Clin Cancer Res 38(1):218

    Google Scholar 

  2. Abdel-Wahab AF, Mahmoud W, Al-Harizy RM (2019) Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 150:104511

    Google Scholar 

  3. Marbaniang C, Kma L (2018) Dysregulation of glucose metabolism by oncogenes and tumor suppressors in cancer cells. Asian Pac J Cancer Prev 19:2377–2390

    Google Scholar 

  4. Libby CJ, Tran AN, Scott SE, Griguer C, Hjelmeland AB (2018) The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells. Biochimica et Biophysica Acta (BBA) 1869(2):175–188

    Google Scholar 

  5. Tabernero A, Medina JM, Giaume C (2006) Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. J Neurochem 99(4):1049–1061

    Google Scholar 

  6. Farahani R, Pina-Benabou MH, Kyrozis A, Siddiq A, Barradas PC, Chiu FC, Rozental R (2005) Alterations in metabolism and gap junction expression may determine the role of astrocytes as “good samaritans” or executioners. Glia 50(4):351–361

    Google Scholar 

  7. Loewenstein WR, Kanno Y (1966) Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature 209(5029):1248–1249

    Google Scholar 

  8. Aasen T, Mesnil M, Naus CC, Lampe PD, Laird DW (2016) Gap junctions and cancer: communicating for 50 years. Nat Rev Cancer 16(12):775

    Google Scholar 

  9. Arun S, Vanisree AJ, Ravisankar S (2016) Connexin 30 downregulates Insulin-like growth factor receptor-1, abolishes Erk and potentiates effects of an IGF-R inhibitor in a glioma cell line. Brain Res 1643:80–90

    Google Scholar 

  10. González-Sánchez A, Jaraíz-Rodríguez M, Domínguez-Prieto M, Herrero-González S, Medina JM, Tabernero A (2016) Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes. Oncotarget 7(31):49819

    Google Scholar 

  11. Sirnes S, Honne H, Ahmed D, Danielsen SA, Rognum TO, Meling GI, Lind GE (2011) DNA methylation analyses of the connexin gene family reveal silencing of GJC1 (Connexin45) by promoter hypermethylation in colorectal cancer. Epigenetics 6(5):602–609

    Google Scholar 

  12. Jayalakshmi J, Vanisree AJ, Ravisankar S, Rama K (2018) Site specific hypermethylation of CpGs in Connexin genes 30, 26 and 43 in different grades of glioma and attenuated levels of their mRNAs. Int J Neurosci 129(3):273–282

    Google Scholar 

  13. Jin Z, Xu S, Yu H, Yang B, Zhao H, Zhao G (2013) miR-125b inhibits Connexin43 and promotes glioma growth. Cell Mol Neurobiol 33(8):1143–1148

    Google Scholar 

  14. Smyth JW, Shaw RM (2013) Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Rep 5(3):611–618

    Google Scholar 

  15. Herrero-González S, Valle-Casuso JC, Sánchez-Alvarez R, Giaume C, Medina JM, Tabernero A (2009) Connexin43 is involved in the effect of endothelin-1 on astrocyte proliferation and glucose uptake. Glia 57(2):222–233

    Google Scholar 

  16. Arun S, Ravisankar S, Vanisree AJ (2017) Implication of connexin30 on the stemness of glioma: connexin30 reverses the malignant phenotype of glioma by modulating IGF-1R, CD133 and cMyc. J Neuro-oncol 135(3):473–485

    Google Scholar 

  17. Galarraga J, Loreck DJ, Graham JF, DeLaPaz RL, Smith BH, Hallgren D, Cummins CJ (1986) Glucose metabolism in human gliomas: Correspondence of in situ and in vitro metabolic rates and altered energy metabolism. Metab Brain Dis 1(4):279–291

    Google Scholar 

  18. Tabernero A, Giaume C, Medina JM (1996) Endothelin-1 regulates glucose utilization in cultured astrocytes by controlling intercellular communication through gap junctions. Glia 16(3):187–195

    Google Scholar 

  19. Naus CC, Bechberger JF, Caveney S, Wilson JX (1991) Expression of gap junction genes in astrocytes and C6 glioma cells. Neurosci Lett 126(1):33–36

    Google Scholar 

  20. Sánchez-Alvarez R, Tabernero A, Medina JM (2004) Endothelin-1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication. J Neurochem 89(3):703–714

    Google Scholar 

  21. Cidad P, Garcia-Nogales P, Almeida A, Bolaños JP (2001) Expression of glucose transporter GLUT3 by endotoxin in cultured rat astrocytes: the role of nitric oxide. J Neurochem 79(1):17–24

    Google Scholar 

  22. Nagamatsu S, Sawa H, Wakizaka A, Hoshino T (1993) Expression of facilitative glucose transporter isoforms in human brain tumors. J Neurochem 61(6):2048–2053

    Google Scholar 

  23. Simmons RA (2017) Cell glucose transport and glucose handling during fetal and neonatal development. In: Fetal and neonatal physiology. Elsevier, Amsterdam, pp 428 435

  24. Vartanian A, Agnihotri S, Wilson MR, Burrell KE, Tonge PD, Alamsahebpour A, Aldape KD (2016) Targeting hexokinase 2 enhances response to radio-chemotherapy in glioblastoma. Oncotarget 7(43):69518

    Google Scholar 

  25. Jha MK, Suk K (2013) Pyruvate dehydrogenase kinase as a potential therapeutic target for malignant gliomas. Brain Tumor Res Treat 1(2):57–63

    Google Scholar 

Download references

Funding

This work was supported by University Grant commission under the award of UGC-BSR Meritorious fellowship (Grant No. GCCO/a-2/UGC-MERITORIOUS/2015/284), New Delhi, India.

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Madras, Chennai, Tamilnadu, 600025, India

    Jayalakshmi Jothi & Vanisree Arambakkam Janardhanam

  2. Department of Neuropathology, Madras Medical College and Government General Hospital, Chennai, Tamilnadu, 600003, India

    K. Rama

Authors
  1. Jayalakshmi Jothi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanisree Arambakkam Janardhanam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Rama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vanisree Arambakkam Janardhanam.

Ethics declarations

Conflict of interest

The authors have indicated they have no potential conflicts of interest to disclose.

Ethical approval

All procedures performed in the studies involving human participants were in accordance with the ethical standard of the Institutional Human Ethics Committee of Government General hospital, Madras Medical College, Chennai, Tamilnadu, India.

Informed consent

Informed consent was obtained from all the individual participant included in the study.

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

Jothi, J., Janardhanam, V.A. & Rama, K. Connexin 30 mediated rewiring of glucose metabolism in rat C6 xenograft and grades of glioma. Mol Cell Biochem 470, 157–164 (2020). https://doi.org/10.1007/s11010-020-03757-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03757-z

Keywords

Search

Navigation