Abstract
Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.
Highlights
Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) and one of the fastest-growing human tumors with nearly 100% growth fraction and the doubling time reaching only 25 hours [1]
We evaluated the therapeutic potential of chemical Serine biosynthesis pathway (SBP) disruption in purpose, mice were subcutaneously inoculated with cells, and xenograftpurpose, mice were subcutaneously inoculated with NAMALWA or RAJI cells, and xenograft-bearing bearing animals with tumor volumes mm were dailyintraperitoneally injected intraperitoneally with animals with tumor volumes exceedingexceeding
We found that the complete loss of phosphoglycerate dehydrogenase (PHGDH)/phosphoserine aminotransferase 1 (PSAT1) expression significantly impaired the proliferation of BL cells in the full medium, suggesting that extracellular availability of this amino acid cannot entirely compensate the biological consequences of PSAT1/PHGDH knockout
Summary
Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) and one of the fastest-growing human tumors with nearly 100% growth fraction and the doubling time reaching only 25 hours [1]. BL is the most common NHL among children, accounting for 50% of all lymphoma cases. Its incidence decreases in older age groups, constituting 1–2% of NHL cases in adults [2,3,4]. It is estimated that 90% of children with BL are cured with intensive chemotherapy, albeit at the cost of considerable toxicity and treatment-related complications [5]. Despite relatively good prognosis for the majority of patients, treatment options for relapsed and refractory BL remain limited, and median overall survival in these cases usually does not exceed 3 months [5,6,7]. The DNA fragments were cloned into pMIG-GFP using XhoI and EcoRI restrictases and introduced into RAJI cells with shRNA-mediated PHGDH knockdown using retroviral transduction
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