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The Inhibition of c-MYC Transcription Factor Modulates the Expression of Glycolytic and Glutaminolytic Enzymes in FaDu Hypopharyngeal Carcinoma Cells

The Inhibition of c-MYC Transcription Factor Modulates the Expression of Glycolytic and Glutaminolytic Enzymes in FaDu Hypopharyngeal Carcinoma Cells

Robert Kleszcz, Jarosław Paluszczak, Violetta Krajka-Kuźniak, Wanda Baer-Dubowska

Adv Clin Exp Med. 2018 Jun;27(6):735-742.

PMID: 29790697

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.
Conclusions:
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP175205091	KG-548		175205-09-1	Price

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