Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism.Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the “Warburg Effect” to reduce energy production in AML blasts.

Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia

“…VDR agonists can also upregulate the expression of fructose‐1,6‐bisphosphatase ( FBP1 ), a gluconeogenesis enzyme involved in the pathway that opposes glycolysis by transforming substrates into glucose. FBP1 expression blocks glycolysis in the blast population, which leads them to cell death (Xu et al , 2022 ).…”

High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia

“…Studies have shown that hematological malignancies can reshape the pathway of glucose and lipid metabolism into aerobic glycolysis so as to support and promote tumor formation [ 5 , 6 ]. Xu et al [ 7 ] found that vitamin D (1,25VD3)-induced overexpression of fructose-1,6-bisphosphatase 1 (FBP1) regulates different metabolic processes in AML, which may serve as an attractive approach to block energy production in AML. Thus, targeted intervention in cancer metabolism has emerged as a potential strategy to ameliorate treatment in AML [ 8 ].…”

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro

“…In a recent study, we performed RNA-sequencing (RNA-Seq) of four different AML-FLT3 (FMS-like tyrosine kinase 3) cell lines and discovered 17,757 genes responding to vitamin D treatment in vitro. In particular, fructose-bisphosphatase 1 ( FBP1 ) stands out as the only gene with a 250-fold increase in expression [ 4 ]. FBP1 is known to encode the gluconeogenic enzyme fructose-1,6-bisphosphatase, which catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate.…”

“…The question of whether FBP1 plays a direct role in preventing leukemic progression and relapse remains to be determined. We recently discovered that vitamin D treatment in vitro significantly induced both FBP1 gene and protein expression intracellularly in various leukemic cell lines, including MV4-11, MOLM-14, and HL60 (a human acute promyelocytic leukemia (APL) cell line) [ 4 ]. Therefore, the therapeutic role of vitamin-D-induced FBP1 overexpression in leukemia remains a viable option that should be further explored.…”