FBP1 modulates cell metabolism of breast cancer cells by inhibiting the expression of HIF-1α

Shi, Lei; He, Chanting; Li, Z; Wang, Z; Zhang, Q

doi:10.4149/neo_2017_407

Cited by 29 publications

(24 citation statements)

References 34 publications

(38 reference statements)

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“…FBP1 has been reported to inhibit HIF-1α activity or expression (27,46). The present study also revealed that knockdown of FBP1 increased the expression of HIF-1α in HCC cells.…”

Section: Discussionsupporting

confidence: 76%

“…FBP1 can inhibit HIF-1α activity via direct interaction with the HIF-1α C-terminus. Furthermore, FBP1 was reported to modulate cell metabolism of breast cancer cells by inhibiting the expression of HIF-1α (46). It was also revealed that knockdown of FBP1 increased the expression of HIF-1α (Fig.…”

Section: Overexpression Of Loxl2 or Knockdown Of Fbp1 Increases The Ementioning

confidence: 87%

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LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial-mesenchymal transition by reducing E-cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose-1, 6-biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail-dependent manner. Overexpression of the point-mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild-type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2-IN-1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF-1α and VEGF in HCC cells, but not in FBP1-knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF-1α/VEGF signaling pathways via the Snail-FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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“…FBP1 has been reported to inhibit HIF-1α activity or expression (27,46). The present study also revealed that knockdown of FBP1 increased the expression of HIF-1α in HCC cells.…”

Section: Discussionsupporting

confidence: 76%

Section: Overexpression Of Loxl2 or Knockdown Of Fbp1 Increases The Ementioning

confidence: 87%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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“…Since the experiments were performed using antibodies that were unable to distinguish between Fbp isozymes (because of the high similarity of Fbp isoforms it is essentially not possible to obtain antibodies that are able to distinguish between the two physiological, globular forms of Fbp isozymes) we tested whether the levels of Ldha and Hif1α in cancer cells depend on Fbp2 amount or the consequences of Fbp2-Hif1α interactions that are not related to glycolysis. It has been previously shown that, in cancer cells, the overexpression of Fbp1 and Fbp2, respectively, stimulated Hif1α degradation [31], suppressed glucose metabolism, and reduced cell proliferation [32]. Our results reveal that, in the KLN205 cells, the partial (about 50%) silencing ( Figure 6A) of Fbp2 expression with shRNA very significantly increased Hif1α and Ldha levels ( Figure 6B,C).…”

Section: Resultssupporting

confidence: 60%

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

Duda

Janczara

McCubrey

et al. 2020

Cells

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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.

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“…Glycolytic antagonist, negative regulator of HIF1α and PKM2 (53). Epigenetic silencing promotes glycolysis, and decreased oxygen consumption and ROS production (37).…”

Section: Fbp1 Oxidative Phosphorylationmentioning

confidence: 99%

“…Master metabolic regulator and transcription factor that upregulates glucose transporters and glycolytic enzymes, including PDK1 and PKM2 (37,53,55,56). Also promoted the shift toward oxidative epithelial-like CSC state (46).…”

Section: Hif-1α Glycolysis Oxidative Phosphorylationmentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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Within heterogeneous tumors, cancer stem cell (CSC) populations exhibit the greatest tumor initiation potential, promote metastasis, and contribute to therapy resistance. For breast cancer specifically, CSCs are identified by CD44 high CD24 low cell surface marker expression and increased aldehyde dehydrogenase activity. In general, bulk breast tumor cells possess altered energetics characterized by aerobic glycolysis. In contrast, breast CSCs appear to have adaptive metabolic plasticity that allows these tumor-initiating cells to switch between glycolysis and oxidative phosphorylation, depending on factors present in the tumor microenvironment (e.g., hypoxia, reactive oxygen species, availability of glucose). In this article, we review the regulatory molecules that may facilitate the metabolic plasticity of breast CSCs. These regulatory factors include epigenetic chromatin modifiers, non-coding RNAs, transcriptional repressors, transcription factors, energy and stress sensors, and metabolic enzymes. Furthermore, breast cancer cells acquire CSC-like characteristics and altered energetics by undergoing epithelial-mesenchymal transition (EMT). This energy costly process is paired with reprogrammed glucose metabolism by epigenetic modifiers that regulate expression of both EMT and other metabolism-regulating genes. The survival advantage imparted to breast CSCs by metabolic plasticity suggests that targeting the factors that mediate the energetic switch should hinder tumorigenesis and lead to improved patient outcomes.

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FBP1 modulates cell metabolism of breast cancer cells by inhibiting the expression of HIF-1α

Cited by 29 publications

References 34 publications

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

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

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

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