6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for transforming growth factor β1-enhanced invasion of Panc1 cells in vitro

Yalçin, Ali; Solakoglu, T. H.; Özcan, Selahattin Can; Guzel, Saime; Peker, Sabire; Çelikler, Serap; Balaban, Başak; Sevinc, Elif Demirdogen; Gurpinar, Yunus; Chesney, Jason

doi:10.1016/j.bbrc.2017.01.178

Cited by 34 publications

(35 citation statements)

References 26 publications

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“…A recent report has also identified PFKFB3 as a key TGF-b1 effector protein in the pancreatic adenocarcinoma cell line Panc1 and demonstrates that siRNAmediated knockdown of PFKFB3 prevents the increase in Fru-2,6-P 2 concentration, lactate production, and glucose consumption, obtained in response to TGF-b1, decreasing glycolysis stimulation in this cell line [52].…”

Section: Discussionmentioning

confidence: 80%

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

et al. 2017

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In human cancers, transforming growth factor-β1 (TGF-β1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-β1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases, that controls the conversion of fructose-6-phosphate (Fru-6-P) to fructose-2,6-bisphosphate (Fru-2,6-P ). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase-1, a rate-limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF-β1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF-β1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6-bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru-2,6-P concentration were reduced when the Smad3, p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA-mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF-β1, one of the hallmarks of transformation. Taken together, these results show that TGF-β1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF-β1 can be one of the main mechanisms mediating the reprogramming of glioma cells.

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Section: Discussionmentioning

confidence: 80%

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

et al. 2017

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“…TGFβ1 enhanced PFKFB3 expression and stimulated glycolysis in Panc1 pancreatic cells. PFKFB3 silencing inhibited TGFβ-induced invasion in this cell line by repressing the expression of SNAI1 [82]. In addition, PFKFB3 was also upregulated by TGFβ1 in glioma cells, resulting in an increase in fructose 2,6-bisphosphate, glucose uptake, glycolytic flux and lactate production [73] (Fig.…”

Section: Tgfβ Signaling Stimulates Glycolysismentioning

confidence: 84%

“…Cancer cells can metabolize lactate as an energy source and also obtain lactate from cells in the tumor microenvironment, thereby maintaining their acidic environment, leading to apoptosis resistance and increased survival and proliferation [87,88]. The increased production of lactate occurs during TGFβinduced EMT [73,76,82]. Lactate dehydrogenase type A (LDHA) plays an important role in catalyzing the conversion of pyruvate into lactate.…”

Section: Tgfβ Signaling Stimulates Glycolysismentioning

confidence: 99%

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Wang

Dijke

Kostidis

et al. 2019

Cell. Mol. Life Sci.

177

144

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Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.

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“…Murine dendritic cell line (DC2.4, kindly provided by Dr De Yang, Center for Cancer Research, National Institutes of Health, US) and DC AFP were kept in house and cultured as described previously 5. Human HCC cell lines, including Hep3B, LM3 and human pancreatic cancer cell (Panc1) were purchased from the American Type Culture Collection biobank and cultured per the manufacturer's instructions 35. Human 293FT cell line used for lentivirus packaging was kept in house and cells were grown at 37 °C in 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% PS (100 U/ml penicillin and 100 μg/ml streptomycin).…”

Section: Methodsmentioning

confidence: 99%

Alarmin augments the antitumor immunity of lentiviral vaccine in ectopic, orthotopic and autochthonous hepatocellular carcinoma mice

Liu

Jing

et al. 2019

Theranostics

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It is a daunting therapeutic challenge to completely eradicate hepatocellular carcinoma (HCC) from patients. Alpha-fetoprotein (AFP) -based vaccines appear promising, however the efficacy needs to be improved. Methods : Here, we explore if fusing high-mobility group nucleosome binding protein 1 (HMGN1), a potent immunoadjuvant, to AFP (lenti-HA) can augment the antitumor immunity of AFP-expressing lentiviral vector (lenti-AFP), a vehicle extensively employed for genetic immunization with high transduction efficacy and good safety profiles. The antitumor immunity of Lenti-HA was systemically assessed in ectopic, orthotopic and autochthonous HCC models. Results : Lenti-HA elicited strong anti-HCC effects in mice and amplified the antitumor immunity of lenti-AFP by reducing effective dose 6-fold. Importantly, lenti-HA induced a robust antitumor immune response with prolonged survival rate and improved the immune and tumor microenvironment in mice with carcinogen-induced autochthonous HCC. Lenti-HA localized primarily to lymphoid organs with no preference for specific immune cell types. Activated dendritic cells (DCs), particularly CD103 + CD11b - DCs, were also actively recruited to lymph nodes in lenti-HA-treated HCC mice. Moreover, lenti-HA-transduced human DCs elicited stronger immune response than lenti-AFP against HCC cells in vitro . Conclusion : Our study demonstrates that HMGN1 augments the antitumor immunity of AFP-expressing lentiviral vaccines in HCC mice and human cells in vitro and thus provides a new therapeutic strategy for HCC.

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6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for transforming growth factor β1-enhanced invasion of Panc1 cells in vitro

Cited by 34 publications

References 26 publications

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Alarmin augments the antitumor immunity of lentiviral vaccine in ectopic, orthotopic and autochthonous hepatocellular carcinoma mice

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