Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells

BACKGROUND: The Warburg effect is one of the hallmarks of cancer and rapidly proliferating cells. It is known that the hypoxia-inducible factor 1-alpha (HIF1A) and MYC proteins cooperatively regulate expression of the HK2 and PDK1 genes, respectively, in the Burkitt lymphoma (BL) cell line P493-6, carrying an inducible MYC gene repression system. However, the mechanism of aerobic glycolysis in BL cells has not yet been fully understood. METHODS AND FINDINGS: Western blot analysis showed that the HIF1A protein was highly expressed in Epstein–Barr virus (EBV)-positive BL cell lines. Using biochemical assays and quantitative PCR (Q-PCR), we found that—unlike in lymphoblastoid cell lines (LCLs)—the MYC protein was the master regulator of the Warburg effect in these BL cell lines. Inhibition of the transactivation ability of MYC had no influence on aerobic glycolysis in LCLs, but it led to decreased expression of MYC-dependent genes and lactate dehydrogenase A (LDHA) activity in BL cells. CONCLUSIONS: Our data suggest that aerobic glycolysis, or the Warburg effect, in BL cells is regulated by MYC expressed at high levels, whereas in LCLs, HIF1A is responsible for this phenomenon.