Abstract:Abstract. Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis. Recently, the catalytic activity-independent function of FBP1, hypoxia-induced factor (HIF) repression in the nucleus, was identified. The aim of the present study was to investigate the association between FBP1 and hypoxia-related gene expression in clear cell renal cell carcinoma (ccRCC). The protein expression levels of FBP1, HIF-1α, HIF-2α, erythropoietin (EPO) and carbonic anhydrase IX (CA9) were assessed by immun… Show more
“…They also found that FBP1 antagonizes glycolytic flux to prevent the Warburg effect from occurring [32]. Ning et al observed higher frequencies of low FBP1 expression in tumor tissues in comparison to healthy tissues, as well as an association between low FBP1 expression and high HIF1α and erythropoietin expression in clear cell renal cell carcinoma [34]. This suggests that the effects of FBP1 may be conserved across tumor types.…”
A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggest that PLK1 may be an important regulator of metabolism maintenance in melanoma cells.
“…They also found that FBP1 antagonizes glycolytic flux to prevent the Warburg effect from occurring [32]. Ning et al observed higher frequencies of low FBP1 expression in tumor tissues in comparison to healthy tissues, as well as an association between low FBP1 expression and high HIF1α and erythropoietin expression in clear cell renal cell carcinoma [34]. This suggests that the effects of FBP1 may be conserved across tumor types.…”
A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggest that PLK1 may be an important regulator of metabolism maintenance in melanoma cells.
“…In human pancreatic adenocarcinoma, high level PKM2 expression interacts with NF-κB and HIF-1α to induce the activation of HIF target gene VEGF. In contrast to FBP1, PKM2 could function as a coactivator to directly bind with HIF-1α by facilitating the recruitment of p300 [ 16 , 37 , 169 ]. Fig.…”
Section: Influence Of Intracellular Metabolites On Hif-α Stability Thmentioning
confidence: 99%
“…Particularly, it has become evident that adaptation in metabolite-driven gene regulation may be a potent hallmark to measure tumorigenesis [ 13 – 15 ]. Hypoxia-inducible factors (HIFs) are heterodimers composed of α subunits and β subunits, where α subunits include HIF-1α, HIF-2α, and the less studied HIF-3α [ 12 , 16 , 17 ]. Under normoxia, two prolines residues of HIF-1α and HIF-2α are hydroxylated by prolyl hydroxylase domain protein 2 (PHD2) and go through ubiquitin-mediated proteolysis via binding to Hippel-Lindau tumor suppressor (VHL) [ 18 ].…”
Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.
“…We noticed a 4‐fold upregulation of FBP1 in group E2 and almost a 3‐fold upregulation in group E1 in the renal cortex. FBP1 is a key gluconeogenesis enzyme and a factor limiting glucose synthesis from non‐sugar compounds (Ning et al, ). Downregulated expression of the LDHB glycolytic enzyme was observed in the renal medulla after administration of fructans in both forms.…”
Section: Discussionmentioning
confidence: 99%
“…We noticed a 4-fold upregulation of FBP1 in group E2 and almost a 3-fold upregulation in group E1 in the renal cortex. FBP1 is a key gluconeogenesis enzyme and a factor limiting glucose synthesis from non-sugar compounds (Ning et al, 2016).…”
The aim of the study was to evaluate the influence of dietary supplementation with inulin extract from chicory root and dried chicory root on the protein profile of the renal cortex and medulla of growing pigs. The experiment was carried out on renal cortex and medulla tissue collected from 24 50‐day‐old PIC x Penarlan P76 crossbred piglets (males). Animals were divided into three dietary groups (n = 8) and fed with a control diet, diet supplemented with 2% inulin extract from chicory root and a diet supplemented with 4% dried chicory root. Kidney samples were collected after 40 days of feeding, and renal cortex and medulla proteins were separated by two‐dimensional electrophoresis. Protein identification was performed using MALDI‐TOF mass spectrometry. The diet supplemented with 2% chicory inulin induced significant expression changes of 20 and 26 protein spots in the renal cortex and medulla respectively. Supplementation with 4% dried chicory root triggered changes in the expression of 44 and 24 proteins in the renal cortex and medulla respectively. Both forms of chicory inulin‐type fructans effectively affected the expression of proteins involved in energy metabolism, heat shock proteins and other chaperones, cytoskeletal and cytoskeleton‐related proteins, as well as other proteins. Additionally, changes in transferrin abundance in both experimental groups suggested the significance of chicory fructan supplementation for iron absorption and bioavailability. In conclusion, 2% inulin extract from chicory root and 4% dried chicory root exerted a similar effect on changes in renal protein expression; however, more pronounced alterations were induced by dried chicory root. Nevertheless, further studies are needed for better understanding the mechanism underlying the effect of chicory inulin‐type fructans and their fermentation end products on the kidneys of growing pigs.
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