Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis
Peiwei Huangyang1, Fuming Li1, Pearl Lee1
1Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
The remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STSs) limits the clinical benefit of targeted therapies. Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. Enforced FBP2 expression inhibits sarcoma cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect," thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic-activity-independent manner by inhibiting the expression of nuclear respiratory factor and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STSs, identifying a potential metabolic vulnerability of this malignancy and possible therapeutic target.
Insights
Soft tissue sarcomas (STSs) silence fructose-1,6-bisphosphatase 2 (FBP2), a key metabolic enzyme. Restoring FBP2 inhibits sarcoma growth by targeting glycolysis and mitochondrial respiration.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer genetics
Background:
- Soft tissue sarcomas (STSs) exhibit significant cellular and genetic heterogeneity.
- This heterogeneity limits the effectiveness of current targeted therapies.
- A common metabolic vulnerability in STSs remains to be identified.
Purpose of the Study:
- To investigate the role of fructose-1,6-bisphosphatase 2 (FBP2) in soft tissue sarcomas.
- To explore FBP2 as a potential therapeutic target for STSs.
- To elucidate the mechanisms by which FBP2 influences sarcoma growth.
Main Methods:
- Analysis of FBP2 expression across various sarcoma subtypes.
- Enforced expression of FBP2 in sarcoma cells and tumors.
- Investigation of FBP2's effects on glycolysis (Warburg effect) and mitochondrial respiration.
- Examination of FBP2's interaction with c-Myc and TFAM expression.
Main Results:
- FBP2 expression is silenced in a wide range of STS subtypes.
- Enforced FBP2 expression inhibits sarcoma cell proliferation and tumor growth.
- Cytosolic FBP2 antagonizes the Warburg effect, reducing glycolysis.
- Nuclear FBP2 inhibits mitochondrial biogenesis and respiration independently of its catalytic activity.
- Nuclear FBP2 represses TFAM expression by interacting with c-Myc at the TFAM locus.
Conclusions:
- FBP2's silencing is a common metabolic feature in STSs.
- FBP2 exhibits a dual inhibitory function against sarcoma growth.
- FBP2 represents a potential metabolic vulnerability and therapeutic target for STSs.
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