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

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.

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