Fructose-1,6-bisphosphatase: From a glucose metabolism enzyme to multifaceted regulator of a cell fate

Gizak, Agnieszka; Duda, Przemysław; Wisniewski, J.; Rakus, Dariusz

doi:10.1016/j.jbior.2019.03.001

Cited by 27 publications

(34 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Fbp1 is the main form of Fbp only in gluconeogenic organs, such as the liver and kidney, and, presumably, in cancers derived from these cells, but in other tissues, the muscle Fbp (Fbp2) is predominantly expressed (for review see: [14]). The results presented here demonstrate that Fbp2 is also the main form of the enzyme in murine and human cancer cells from the KLN205 and A549 line ( Figure 4A,C).…”

Section: Resultsmentioning

confidence: 99%

“…The ubiquitous expression of Fbp2 (for review see: [14]) and its up-regulation in cancer cells co-cultured with fibroblasts, prompted us to check if Fbp2 may interact with Hif1α and to test the consequences of such hypothetical interactions.…”

Section: Resultsmentioning

confidence: 99%

“…This dual role of Fbp2-the stabilization of the Hif1α transcriptional activity in the nucleus and the promotion of the transcription factor for the degradation in cytoplasm-may result from unique structural and kinetic properties of the isozyme. Fbp2 is over an order of magnitude that is more sensitive than Fbp1 to allosteric inhibitors, AMP, and NAD + (for review see [14]). In contrast to Fbp1, Fbp2 is also strongly inhibited by calcium ions [33].…”

Section: Resultsmentioning

confidence: 99%

“…The Fbp2 oligomerization state, and thus its role/interactions in a cell, is regulated by AMP and NAD + (for review see: [14]), both of which are crucial indicators of cellular metabolic conditions. Therefore, we hypothesize that the hypoxia/Hif1α-dependent regulation of the metabolism in cancer is modulated through Fbp2, and is based on the energy and redox state of a cell.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts

Duda

Janczara

McCubrey

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts’ ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactate and pyruvate—a process known as the reverse Warburg effect. We demonstrate that these changes result from a fibroblasts-stimulated increase in the expression of fructose bisphosphatase (Fbp) in cancer cells and the consequent modulation of Hif1α function. We show that, in contrast to current beliefs, in lung cancer cells, the predominant and strong interaction with the Hif1α form of Fbp is not the liver (Fbp1) but in the muscle (Fbp2) isoform. Since Fbp2 oligomerization state and thus, its role is regulated by AMP and NAD+—crucial indicators of cellular metabolic conditions—we hypothesize that the Hif1α-dependent regulation of the metabolism in cancer is modulated through Fbp2, a sensor of the energy and redox state of a cell.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts

Duda

Janczara

McCubrey

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are other inhibitors including, MB07803 (Phase II), Anilinoquinazolines, VK0612 (Phase II), and managlinat dialanetil (Phase II) are in clinical development. 55 Glutamine Fructose-6-Phosphate Amidotransferase (GFAT) Inhibitor T2DM characterized by insulin resistance, decrease insulin secretion and increased glucose production. Several studies have shown hyperglycemia contributes to developing insulin resistance and vascular complication, even though the biochemical mechanisms causing these effects have not yet understood.…”

Section: Fructose 1 6-bisphosphatase Inhibitorsmentioning

confidence: 99%

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

Belete¹

2020

JEP

View full text Add to dashboard Cite

Type 2 diabetes (T2DM) is a chronic metabolic disorder. Impaired insulin secretion, enhanced hepatic glucose production, and suppressed peripheral glucose use are the main defects responsible for developing the disease. Besides, the pathophysiology of T2DM also includes enhanced glucagon secretion, decreased incretin secretion, increased renal glucose reabsorption, and adipocyte, and brain insulin resistance. The increasing prevalence of T2DM in the world beseeches an urgent need for better treatment options. The antidiabetic drugs focus on control of blood glucose concentration, but the future treatment goal is to delay disease progression and treatment failure, which causes poorer glycemic regulation. Recent treatment approaches target on several novel pathophysiological defects present in T2DM. Some of the promising novel targets being under clinical development include those that increase insulin sensitization (antagonists of glucocorticoids receptor), decreasing hepatic glucose production (glucagon receptor antagonist, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase). This review summarizes studies that are available on novel targets being studied to treat T2DM with an emphasis on the small molecule drug design. The experience gathered from earlier studies and knowledge of T2DM pathways can guide the anti-diabetic drug development toward the discovery of drugs essential to treat T2DM.

show abstract

Nuclear Fructose‐1,6‐Bisphosphate Inhibits Tumor Growth and Sensitizes Chemotherapy by Targeting HMGB1

Zhang

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Metabolites are important for cell fate determination. Fructose‐1,6‐bisphosphate (F1,6P) is the rate‐limiting product in glycolysis and the rate‐limiting substrate in gluconeogenesis. Here, it is discovered that the nuclear‐accumulated F1,6P impairs cancer cell viability by directly binding to high mobility group box 1 (HMGB1), the most abundant non‐histone chromosome structural protein with paradoxical roles in tumor development. F1,6P disrupts the association between the HMGB1 A‐box and C‐tail by targeting K43/K44 residues, inhibits HMGB1 oligomerization, and stabilizes P53 protein by increasing P53–HMGB1 interaction. Moreover, F1,6P lowers the affinity of HMGB1 for DNA and DNA adducts, which sensitizes cancer cells to chemotherapeutic drug(s)‐induced DNA replication stress and DNA damage. Concordantly, F1,6P resensitizes cancer cells with chemotherapy resistance, impairs tumor growth and enhances chemosensitivity in mice, and impedes the growth of human tumor organoids. These findings reveal a novel role for nuclear‐accumulated F1,6P and underscore the potential utility of F1,6P as a drug for cancer therapy.

show abstract

Fructose-1,6-bisphosphatase: From a glucose metabolism enzyme to multifaceted regulator of a cell fate

Cited by 27 publications

References 70 publications

The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts

The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

Nuclear Fructose‐1,6‐Bisphosphate Inhibits Tumor Growth and Sensitizes Chemotherapy by Targeting HMGB1

Contact Info

Product

Resources

About