Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.4)
Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 6, June, p. 735–742

doi: 10.17219/acem/68979

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

Robert Kleszcz1,A,B,C,D, Jarosław Paluszczak1,A,B,C,E,F, Violetta Krajka-Kuźniak1,B, Wanda Baer-Dubowska1,C,E,F

1 Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poland

Abstract

Background. Cancer cells are dependent on aerobic glycolysis for energy production and increased glutamine consumption. HIF-1α and c-MYC transcription factors regulate the expression of glycolytic and glutaminolytic genes. Their activity may be repressed by SIRT6. Head and neck carcinomas show frequent activation of c-MYC function and SIRT6 down-regulation, which contributes to a strong dependence on glucose and glutamine availability.
Objectives. The aim of this study was to compare the influence of HIF-1α and c-MYC inhibitors (KG-548 and 10058-F4, respectively) and potential SIRT6 inducers – resveratrol and its synthetic derivative DMU-212 with the effect of glycolysis and glutaminolysis inhibitors (2-deoxyglucose and aminooxyacetic acid, respectively) on the metabolism and expression of metabolic enzymes in FaDu hypopharyngeal carcinoma cells.
Material and Methods. Cell viability was assessed by means of an MTT assay. Quantitative PCR was performed to evaluate the expression of SIRT6, HIF-1α, c-MYC, GLUT1, SLC1A5, HK2, PFKM, PKM2, LDHA, GLS, and GDH. The release of glycolysis and glutaminolysis end-products into the culture medium – lactate and ammonia, respectively – was assessed using standard colorimetric assays.
Results. Lactate production was significantly inhibited by 10058-F4, KG-548, and 2-deoxyglucose. Moreover, 10058-F4 strongly reduced the amount of ammonia release. The effects of 10058-F4 activity can be attributed to a reduction in the expression of PKM2 and LDHA. On the other hand, the induction of SIRT6 expression by resveratrol and DMU-212 was not associated with significant modulation of the expression of metabolic enzymes.
Conclusion. Overall, the results of this study indicate that the inhibition of c-MYC may be considered to be a promising strategy of the modulation of cancer-related metabolic changes in head and neck carcinomas.

Key words

c-MYC, energy metabolism, the Warburg effect, 10058-F4, FaDu cells

References (32)

  1. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314.
  2. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646–674.
  3. Samudio I, Fiegl M, Andreeff M. Mitochondrial uncoupling and the Warburg effect: Molecular basis for the reprogramming of cancer cell metabolism. Cancer Res. 2009;69:2163–2166.
  4. Ward PS, Thompson CB. Signaling in control of cell growth and metabolism. Cold Spring Harb Perspect Biol. 2012;4(7):a006783. doi: 10.1101/cshperspect.a006783
  5. Dando I, Fiorini C, Pozza ED, et al. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochim Biophys Acta. 2013;1833:672–679.
  6. Wang HJ, Hsieh YJ, Cheng WC, et al. MJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci USA. 2014;111:279–284.
  7. Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30:2986–2996.
  8. Hammoudi N, Ahmed KB, Garcia-Prieto C, Huang P. Metabolic alterations in cancer cells and therapeutic implications. Chin J Cancer. 2011;30:508–525.
  9. Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–8930.
  10. Sandulache VC, Myers JN. Altered metabolism in head and neck squamous cell carcinoma: An opportunity for identification of novel biomarkers and drug targets. Head Neck. 2012;34:282–290.
  11. Wise DR, DeBerardinis RJ, Mancuso A, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–18787.
  12. Gao P, Tchernyshyov I, Chang TC, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–765.
  13. Kleszcz R, Paluszczak J, Baer-Dubowska W. Targeting aberrant cancer metabolism – The role of sirtuins. Pharmacol Rep. 2015;67:1068–1080.
  14. Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci. 2011;124:833–838.
  15. Zhong L, Mostoslavsky R. SIRT6: A master epigenetic gatekeeper of glucose metabolism. Transcription. 2010;1:17–21.
  16. Sebastián C, Zwaans BM, Silberman DM, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151:1185–1199.
  17. Lyssiotis CA, Cantley LC. SIRT6 puts cancer metabolism in the driver’s seat. Cell. 2012;151:1155–1156.
  18. Lai CC, Lin PM, Lin SF, et al. Altered expression of SIRT gene family in head and neck squamous cell carcinoma. Tumor Biol. 2013;34:1847–1854.
  19. Kim HS, Xiao C, Wang RH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010;12:224–236.
  20. Rezende TM, de Souza Freire M, Franco OL. Head and neck cancer: Proteomic advances and biomarker achievements. Cancer. 2010;116:4914–4925.
  21. Pignon JP, le Maître A, Maillard E, Bourhis J. MACH-NC Collaborative Group: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92:4–14.
  22. Sandulache VC, Ow TJ, Pickering CR, et al. Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. Cancer. 2011;117:2926–2938.
  23. Dang CV. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 2010;70:859–862.
  24. Cai J, Zuo Y, Wang T, Cao Y, Cai R, Chen FL. A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity. Oncogene. 2016;35:4949-4956.
  25. Price NL, Gomes AP, Ling AJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–690.
  26. Sobhakumari A, Orcutt KP, Love-Homan L, et al. 2-Deoxy-d-glucose suppresses the in vivo antitumor efficacy of erlotinib in head and neck squamous cell carcinoma cells. Oncol Res. 2016;24:55–64.
  27. Pietzke M, Zasada C, Mudrich S, Kempa S. Decoding the dynamics of cellular metabolism and the action of 3-bromopyruvate and 2-deoxyglucose using pulsed stable isotope-resolved metabolomics. Cancer Metab. 2014;2:9.
  28. Warmoes MO, Locasale JW. Heterogeneity of glycolysis in cancers and therapeutic opportunities. Biochem Pharmacol. 2014;92:12–21.
  29. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene. 2006;25:4633–4646.
  30. Kurtoglu M, Gao N, Shang J, et al. Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. Mol Cancer Ther. 2007;6:3049–3058.
  31. Coller HA. Is cancer a metabolic disease? Am J Pathol. 2014;184:4–17.
  32. Korangath P, Teo WW, Sadik H, et al. Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clin Cancer Res. 2015;21:3263–3273.
© Wroclaw Medical University