FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.

The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect.

Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

Kinetic properties of pig (Sus scrofa domestica) and bovine (Bos taurus) D-fructose-1,6-bisphosphate 1-phosphohydrolase (F1,6BPase): liver-like isozymes in mammalian lung tissue.

F1,6BPases from porcine and bovine lung were isolated and their kinetic properties were determined. Ks, Kis and beta were determined assuming partial-noncompetitive inhibition (simple intersecting hyperbolic noncompetitive inhibition) of the enzyme by the substrate. Values for Ks were 4.1 and 4.4 microM for porcine and bovine F1,6BPase, respectively and values for 1 were close to 0.55 in both cases. Kis were 9 and 15 microM for porcine and bovine F1,6BPase, respectively. I0.5 for AMP were determined as 7 microM for pig enzyme and 14 microM for F1,6BPase from bovine lung. The enzymes were inhibited by F2,6BP with Ki's of 0.19 and 0.21 microM for porcine and bovine enzymes, respectively. In the presence of AMP concentration equal to I0.5, the Ki values for pig and bovine enzymes were 0.07 and 0.09 microM, respectively. The levels of F2,6BP, AMP and antioxidant enzymes activities in pig and bovine lung tissues were also determined. The cDNA coding sequence of pig lung F1,6BPase1 showed a high homology with pig liver enzyme, differing only in four positions (G/C-63, T/A-808, G/C-884 and T/A-1005) resulting in a single amino acid substitution (Gly-295 for Ala-295). It is hypothesized that the lung F1,6BPase participates in gluconeogenesis, surfactant synthesis and antioxidant reactions.

Gas-exchange analysis of chloroplastic fructose-1,6-bisphosphatase antisense potatoes at different air humidities and at elevated CO(2).

Gas-exchange measurements were performed to analyze the leaf conductances and assimilation rates of potato (Solanum tuberosum L. cv. Desireé) plants expressing an antisense construct against chloroplastic fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) in response to increasing photon flux densities, different relative air humidities and elevated CO(2) concentrations. Assimilation rates (A) and transpiration rates (E) were observed during a stepwise increase of photon flux density. These experiments were carried out under atmospheric conditions and in air containing 500 micromol mol(-1) CO(2). In both gas atmospheres, two levels of relative air humidity (60-70% and 70-80%) were applied in different sets of measurements. Intercellular CO(2) concentration, leaf conductance, air-to-leaf vapour pressure deficit, and instantaneous water-use efficiency (A/E) were determined. As expected, assimilation rates of the FBPase antisense plants were significantly reduced as compared to the wild type. Saturation of assimilation rates in transgenic plants occurred at a photon flux density of 200 micromol m(-2) s(-1), whereas saturation in wild type plants was observed at 600 micromol m(-2) s(-1). Elevated ambient CO(2) levels did not effect assimilation rates of transgenic plants. At 70-80% relative humidity and atmospheric CO(2) concentration the FBPase antisense plants had significantly higher leaf conductances than wild-type plants while no difference emerged at 60-70%. These differences in leaf conductance vanished at elevated levels of ambient CO(2). Stomatal response to different relative air humidities was not affected by mesophyll photosynthetic activity. It is suggested that the regulation of stomatal opening upon changes in photon flux density is merely mediated by a signal transmitted from mesophyll cells, whereas the intercellular CO(2) concentration plays a minor role in this kind of stomatal response. The results are discussed with respect to stomatal control by environmental parameters and mesophyll photosynthesis.

Function, structure and evolution of fructose-1,6-bisphosphatase.

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate is a key reaction of carbohydrate metabolism. The enzyme that catalyzes this reaction, fructose-1,6-bisphosphatase, appears to be present in all forms of living organisms. Regulation of the enzyme activity, however, occurs by a variety of distinct mechanisms. These include AMP inhibition (most sources), cyclic AMP-dependent phosphorylation (yeast), and light-dependent activation (chloroplast). In this short review, we have analyzed the function of several fructose-1,6-bisphosphatases and we have made a comparison of partial amino acid sequences obtained from the enzymes of the yeast Saccharomyces cerevisiae, Escherichia coli, and spinach chloroplasts with the known entire amino acid sequence of a mammalian gluconeogenic fructose-1,6-bisphosphatase. These results demonstrate a very high degree of sequence conservation, suggesting a common evolutionary origin for all fructose-1,6-bisphosphatases.